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BI denies allegations about dabigatran
Credit: CDC
A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).
The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company, Boehringer Ingelheim (BI), has denied these allegations.
“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.
“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa. Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”
Concerns about the RE-LY trial
One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.
The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.
The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.
The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.
BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.
In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.
BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.
Allegations of withheld data
Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.
The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.
The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.
BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.
However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.
Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.
The role of regulators, physicians, and patients
A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.
The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.
The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.
The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug. 
Credit: CDC
A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).
The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company, Boehringer Ingelheim (BI), has denied these allegations.
“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.
“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa. Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”
Concerns about the RE-LY trial
One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.
The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.
The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.
The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.
BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.
In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.
BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.
Allegations of withheld data
Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.
The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.
The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.
BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.
However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.
Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.
The role of regulators, physicians, and patients
A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.
The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.
The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.
The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.
Credit: CDC
A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).
The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company, Boehringer Ingelheim (BI), has denied these allegations.
“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.
“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa. Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”
Concerns about the RE-LY trial
One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.
The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.
The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.
The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.
BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.
In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.
BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.
Allegations of withheld data
Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.
The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.
The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.
BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.
However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.
Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.
The role of regulators, physicians, and patients
A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.
The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.
The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.
The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.
NICE expands recommended use for prasugrel
Credit: Mass. General Hospital
The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).
NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).
The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.
“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.
“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”
The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.
The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.
For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel. 
Credit: Mass. General Hospital
The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).
NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).
The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.
“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.
“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”
The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.
The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.
For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel.
Credit: Mass. General Hospital
The UK’s National Institute for Health and Care Excellence (NICE) has decided to expand its recommendation for the antiplatelet agent prasugrel (Efient).
NICE’s new guidance recommends prasugrel in combination with aspirin to prevent thrombosis in patients with unstable angina, ST segment elevation myocardial infarction (STEMI), or non-ST segment elevation myocardial infarction (NSTEMI) who are undergoing percutaneous coronary intervention (PCI).
The previous guidance recommended prasugrel in combination with aspirin for patients with acute coronary syndromes undergoing PCI only when immediate primary PCI for STEMI was necessary, stent thrombosis occurred during clopidogrel treatment, or the patient had diabetes.
“[A NICE committee] assessed the clinical and cost effectiveness of prasugrel, noting that, since the original guidance was published in 2009, NICE has also published guidance on the use of ticagrelor for the same indication, and the price of another drug, clopidogrel, has reduced as generic versions have become available,” said Carole Longson, Director of the Centre for Health Technology Evaluation at NICE.
“Taking these factors into consideration, we are now recommending prasugrel as an option for more people with acute coronary syndromes than our previous guidance. The committee also heard from clinical experts that the faster action of prasugrel compared to clopidogrel could be an advantage for STEMI patients who need immediate percutaneous coronary intervention. The guidance also recommends prasugrel as an option for people with NSTEMI and unstable angina, with or without diabetes.”
The price of prasugrel is £47.56 per 28-tab pack (excluding value-added tax). The cost of treatment for 12 months is £628.48 (excluding value-added tax). Costs may vary in different settings because of negotiated procurement discounts.
The incremental cost-effectiveness ratios for all 4 of the patient subgroups reviewed (STEMI with diabetes, STEMI without diabetes, unstable angina or NSTEMI with diabetes, unstable angina and NSTEMI without diabetes) were lower than £20,000 per quality-adjusted life-year gained.
For patients with unstable angina or NSTEMI and diabetes, prasugrel proved more effective and less costly than clopidogrel.
FDA approves idelalisib for CLL, SLL and FL
The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).
The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.
The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.
This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.
Idelalisib in CLL: Results of a phase 3 study
The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.
The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Idelalisib in FL and SLL: Results of a phase 2 study
Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).
The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.
The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.
The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).
Improvements in patient survival or disease-related symptoms have not been established.
In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).
About idelalisib: Dosing, boxed warning and REMS
Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.
The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.
Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.
The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.
The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).
The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.
The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.
This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.
Idelalisib in CLL: Results of a phase 3 study
The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.
The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Idelalisib in FL and SLL: Results of a phase 2 study
Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).
The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.
The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.
The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).
Improvements in patient survival or disease-related symptoms have not been established.
In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).
About idelalisib: Dosing, boxed warning and REMS
Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.
The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.
Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.
The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.
The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).
The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.
The FDA’s accelerated approval program allows for approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.
This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.
Idelalisib in CLL: Results of a phase 3 study
The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.
The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Idelalisib in FL and SLL: Results of a phase 2 study
Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).
The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.
The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.
The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).
Improvements in patient survival or disease-related symptoms have not been established.
In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).
About idelalisib: Dosing, boxed warning and REMS
Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.
The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.
Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.
The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.
Drug approved to treat NHL in Israel
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.
FDA warns public of non-sterile products
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.
Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.
NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”
FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.
The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.
The FDA is not aware of recent reports of illness associated with the use of these products.
Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.
Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.
Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.
NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”
FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.
The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.
The FDA is not aware of recent reports of illness associated with the use of these products.
Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.
Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.
Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.
NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”
FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.
The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.
The FDA is not aware of recent reports of illness associated with the use of these products.
Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.
Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.
FDA approves new product for chronic ITP
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
FDA approves product to treat attacks in HAE
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
FDA warns of non-sterile drugs
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.
Administration of a non-sterile product may result in serious infection or death.
Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”
FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.
The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.
The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.
The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.
To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.
Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.
Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.
Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.
Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.
Administration of a non-sterile product may result in serious infection or death.
Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”
FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.
The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.
The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.
The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.
To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.
Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.
Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.
Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.
Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.
Credit: Bill Branson
The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.
Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.
Administration of a non-sterile product may result in serious infection or death.
Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”
FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.
The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.
The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.
The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.
To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.
Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.
Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.
Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.
Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.
Product recalled due to mold contamination
Image courtesy of Hospira
Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).
The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.
An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.
Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.
However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.
Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.
The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.
This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.
Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.
For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or medcom@hospira.com.
To report adverse events or product complaints, contact Hospira Global
Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or
medcom@hospira.com.
Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
Image courtesy of Hospira
Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).
The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.
An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.
Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.
However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.
Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.
The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.
This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.
Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.
For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or medcom@hospira.com.
To report adverse events or product complaints, contact Hospira Global
Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or
medcom@hospira.com.
Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
Image courtesy of Hospira
Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).
The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.
An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.
Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.
However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.
Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.
The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.
This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.
Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.
For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or medcom@hospira.com.
To report adverse events or product complaints, contact Hospira Global
Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or
medcom@hospira.com.
Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
FDA approves drug for refractory Glanzmann’s Thrombasthenia
Credit: Piotr Bodzek
The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.
GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.
The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.
Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.
The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.
The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.
The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.
Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).
NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.
Credit: Piotr Bodzek
The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.
GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.
The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.
Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.
The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.
The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.
The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.
Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).
NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.
Credit: Piotr Bodzek
The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.
GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.
The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.
Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.
The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.
The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.
The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.
Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).
NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.