Pharmacy

Doctor and patient

Credit: CDC

The medical technology company CareFusion has announced a Class I recall of its Alaris Pump model 8100, software version 9.1.18.

This large-volume infusion pump is used for the delivery of fluids, medicines, blood, and blood products.

Version 9.1.18 of the Alaris Pump model 8100 is being recalled due to the possibility of a software failure in which the pump module will not properly delay an infusion when the “Delay Until” option or “Multidose” feature is used.

There have been no reports of adverse events or deaths related to this malfunction, but it does pose risks. CareFusion has received 1 report where the device malfunctioned when the “Delay Until” option was selected.

The software failure also prevents the pump from properly delivering a multidose infusion under the following conditions:

• When the first dose is programmed to infuse when the system time is earlier than 7 pm and a subsequent dose is intended to infuse between 7 pm and 11:59 pm
• When the first dose is programmed to infuse when the system time is between 7 pm and 11:59 pm and a subsequent dose is intended to infuse between 12 am and 6:59 pm the next day.

If the infusion starts earlier or later than intended and is not immediately detected and stopped, serious injury or death could result. Therefore, healthcare professionals should not use the Alaris Pump module “Delay Until” option or the “Multidose” option.

However, CareFusion said it has identified the root cause of the issue and recommends that the previous Alaris Pump module software version 9.1.17 be installed to address this recall. The company said it will contact all affected customers to schedule the installation of software version 9.1.17.

As an interim guidance, customers may update their dataset to disable both “Delay” options (“Delay Until” and “Delay For”) and/or the “Multidose” option across all profiles to prevent the use of these features. These are shared configurations with the Alaris Syringe module and, if disabled, would prevent use of these features with the Alaris Syringe module as well.

For more information on this recall, see CareFusion’s recall notice, or contact the CareFusion Support Center at 888-562-6018 or SupportCenter@carefusion.com.

To report adverse reactions or quality problems associated with this product, visit the Food and Drug Administration’s MedWatch website.

Doctor and patient

Credit: CDC

The medical technology company CareFusion has announced a Class I recall of its Alaris Pump model 8100, software version 9.1.18.

This large-volume infusion pump is used for the delivery of fluids, medicines, blood, and blood products.

Version 9.1.18 of the Alaris Pump model 8100 is being recalled due to the possibility of a software failure in which the pump module will not properly delay an infusion when the “Delay Until” option or “Multidose” feature is used.

There have been no reports of adverse events or deaths related to this malfunction, but it does pose risks. CareFusion has received 1 report where the device malfunctioned when the “Delay Until” option was selected.

The software failure also prevents the pump from properly delivering a multidose infusion under the following conditions:

• When the first dose is programmed to infuse when the system time is earlier than 7 pm and a subsequent dose is intended to infuse between 7 pm and 11:59 pm
• When the first dose is programmed to infuse when the system time is between 7 pm and 11:59 pm and a subsequent dose is intended to infuse between 12 am and 6:59 pm the next day.

If the infusion starts earlier or later than intended and is not immediately detected and stopped, serious injury or death could result. Therefore, healthcare professionals should not use the Alaris Pump module “Delay Until” option or the “Multidose” option.

However, CareFusion said it has identified the root cause of the issue and recommends that the previous Alaris Pump module software version 9.1.17 be installed to address this recall. The company said it will contact all affected customers to schedule the installation of software version 9.1.17.

As an interim guidance, customers may update their dataset to disable both “Delay” options (“Delay Until” and “Delay For”) and/or the “Multidose” option across all profiles to prevent the use of these features. These are shared configurations with the Alaris Syringe module and, if disabled, would prevent use of these features with the Alaris Syringe module as well.

For more information on this recall, see CareFusion’s recall notice, or contact the CareFusion Support Center at 888-562-6018 or SupportCenter@carefusion.com.

To report adverse reactions or quality problems associated with this product, visit the Food and Drug Administration’s MedWatch website.

Doctor and patient

Credit: CDC

The medical technology company CareFusion has announced a Class I recall of its Alaris Pump model 8100, software version 9.1.18.

This large-volume infusion pump is used for the delivery of fluids, medicines, blood, and blood products.

Version 9.1.18 of the Alaris Pump model 8100 is being recalled due to the possibility of a software failure in which the pump module will not properly delay an infusion when the “Delay Until” option or “Multidose” feature is used.

There have been no reports of adverse events or deaths related to this malfunction, but it does pose risks. CareFusion has received 1 report where the device malfunctioned when the “Delay Until” option was selected.

The software failure also prevents the pump from properly delivering a multidose infusion under the following conditions:

• When the first dose is programmed to infuse when the system time is earlier than 7 pm and a subsequent dose is intended to infuse between 7 pm and 11:59 pm
• When the first dose is programmed to infuse when the system time is between 7 pm and 11:59 pm and a subsequent dose is intended to infuse between 12 am and 6:59 pm the next day.

If the infusion starts earlier or later than intended and is not immediately detected and stopped, serious injury or death could result. Therefore, healthcare professionals should not use the Alaris Pump module “Delay Until” option or the “Multidose” option.

However, CareFusion said it has identified the root cause of the issue and recommends that the previous Alaris Pump module software version 9.1.17 be installed to address this recall. The company said it will contact all affected customers to schedule the installation of software version 9.1.17.

As an interim guidance, customers may update their dataset to disable both “Delay” options (“Delay Until” and “Delay For”) and/or the “Multidose” option across all profiles to prevent the use of these features. These are shared configurations with the Alaris Syringe module and, if disabled, would prevent use of these features with the Alaris Syringe module as well.

For more information on this recall, see CareFusion’s recall notice, or contact the CareFusion Support Center at 888-562-6018 or SupportCenter@carefusion.com.

To report adverse reactions or quality problems associated with this product, visit the Food and Drug Administration’s MedWatch website.

TPN components

The US Food and Drug Administration (FDA) has announced a Class I recall of Baxter Corporation Englewood’s ABACUS Total Parenteral Nutrition (TPN) Calculation Software, versions 3.1, 3.0, 2.1, and 2.0.

Baxter has received 2 reports of malfunctioning software and said errors with this software may cause adverse effects.

ABACUS TPN Calculation Software is a Windows-based software application used by pharmacists to calculate or order TPN formulas.

The errors explained

Due to software failures, the following errors may occur:

• ABACUS v3.1 may calculate quantities of electrolytes that are double the expected values during the creation of TPN orders.
• ABACUS v3.1 may automatically add additional sterile water to a formula equal to the volume of a premix, resulting in an over-dilution.
• All software versions of ABACUS software display the calcium phosphate curve points for Premasol incorrectly.
• All software versions of ABACUS may display an inaccurate estimation for calcium and phosphate precipitation in certain circumstances where multiple ingredients provide calcium.

If any of these failures occur, patients may be at risk of developing overdose symptoms. The symptoms are varied and depend on the type of software failure and composition of the fluid being compounded.

Symptoms may be non-specific and include nausea, vomiting, dizziness, or fatigue. Some more severe symptoms include cardiac arrhythmia, pulmonary edema, congestive heart failure, and seizures. A fatal outcome is possible, especially in the high-risk population.

Actions to take

Baxter is recommending that customers contact the company to ensure the ABACUS software is configured correctly.

Customers with a software version earlier than 3.1 will have software version 3.1 installed, which addresses the issues that prompted the recall. In addition, Baxter Support Services will schedule upgrades and assist customers with establishing the proper ABACUS configuration in the customers’ facilities.

Baxter has also requested that customers follow safe compounding practices. Namely, use the “Summary” button to verify the order against the calculated amounts prior to completing the order.

In addition, verify that the ordered ingredients and quantities displayed in the software and printed on the Bag label and the Solution Formula label match the PN prescription prior to preparation. And use a filter for administration of a PN bag.

For more information on the recall, see the FDA’s recall notice, or contact Baxter at 303-617-2242. For technical support, call 1-800-678-2292 or email COtechsupport@baxter.com.

To report adverse reactions or quality problems related to this product, visit the FDA’s MedWatch website.

TPN components

The US Food and Drug Administration (FDA) has announced a Class I recall of Baxter Corporation Englewood’s ABACUS Total Parenteral Nutrition (TPN) Calculation Software, versions 3.1, 3.0, 2.1, and 2.0.

Baxter has received 2 reports of malfunctioning software and said errors with this software may cause adverse effects.

ABACUS TPN Calculation Software is a Windows-based software application used by pharmacists to calculate or order TPN formulas.

The errors explained

Due to software failures, the following errors may occur:

• ABACUS v3.1 may calculate quantities of electrolytes that are double the expected values during the creation of TPN orders.
• ABACUS v3.1 may automatically add additional sterile water to a formula equal to the volume of a premix, resulting in an over-dilution.
• All software versions of ABACUS software display the calcium phosphate curve points for Premasol incorrectly.
• All software versions of ABACUS may display an inaccurate estimation for calcium and phosphate precipitation in certain circumstances where multiple ingredients provide calcium.

If any of these failures occur, patients may be at risk of developing overdose symptoms. The symptoms are varied and depend on the type of software failure and composition of the fluid being compounded.

Symptoms may be non-specific and include nausea, vomiting, dizziness, or fatigue. Some more severe symptoms include cardiac arrhythmia, pulmonary edema, congestive heart failure, and seizures. A fatal outcome is possible, especially in the high-risk population.

Actions to take

Baxter is recommending that customers contact the company to ensure the ABACUS software is configured correctly.

Customers with a software version earlier than 3.1 will have software version 3.1 installed, which addresses the issues that prompted the recall. In addition, Baxter Support Services will schedule upgrades and assist customers with establishing the proper ABACUS configuration in the customers’ facilities.

Baxter has also requested that customers follow safe compounding practices. Namely, use the “Summary” button to verify the order against the calculated amounts prior to completing the order.

In addition, verify that the ordered ingredients and quantities displayed in the software and printed on the Bag label and the Solution Formula label match the PN prescription prior to preparation. And use a filter for administration of a PN bag.

For more information on the recall, see the FDA’s recall notice, or contact Baxter at 303-617-2242. For technical support, call 1-800-678-2292 or email COtechsupport@baxter.com.

To report adverse reactions or quality problems related to this product, visit the FDA’s MedWatch website.

TPN components

The US Food and Drug Administration (FDA) has announced a Class I recall of Baxter Corporation Englewood’s ABACUS Total Parenteral Nutrition (TPN) Calculation Software, versions 3.1, 3.0, 2.1, and 2.0.

Baxter has received 2 reports of malfunctioning software and said errors with this software may cause adverse effects.

ABACUS TPN Calculation Software is a Windows-based software application used by pharmacists to calculate or order TPN formulas.

The errors explained

Due to software failures, the following errors may occur:

• ABACUS v3.1 may calculate quantities of electrolytes that are double the expected values during the creation of TPN orders.
• ABACUS v3.1 may automatically add additional sterile water to a formula equal to the volume of a premix, resulting in an over-dilution.
• All software versions of ABACUS software display the calcium phosphate curve points for Premasol incorrectly.
• All software versions of ABACUS may display an inaccurate estimation for calcium and phosphate precipitation in certain circumstances where multiple ingredients provide calcium.

If any of these failures occur, patients may be at risk of developing overdose symptoms. The symptoms are varied and depend on the type of software failure and composition of the fluid being compounded.

Symptoms may be non-specific and include nausea, vomiting, dizziness, or fatigue. Some more severe symptoms include cardiac arrhythmia, pulmonary edema, congestive heart failure, and seizures. A fatal outcome is possible, especially in the high-risk population.

Actions to take

Baxter is recommending that customers contact the company to ensure the ABACUS software is configured correctly.

Customers with a software version earlier than 3.1 will have software version 3.1 installed, which addresses the issues that prompted the recall. In addition, Baxter Support Services will schedule upgrades and assist customers with establishing the proper ABACUS configuration in the customers’ facilities.

Baxter has also requested that customers follow safe compounding practices. Namely, use the “Summary” button to verify the order against the calculated amounts prior to completing the order.

In addition, verify that the ordered ingredients and quantities displayed in the software and printed on the Bag label and the Solution Formula label match the PN prescription prior to preparation. And use a filter for administration of a PN bag.

For more information on the recall, see the FDA’s recall notice, or contact Baxter at 303-617-2242. For technical support, call 1-800-678-2292 or email COtechsupport@baxter.com.

To report adverse reactions or quality problems related to this product, visit the FDA’s MedWatch website.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.

The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.

Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.

The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.

The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.

Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.

Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.

These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.

A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.

The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.

Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.

The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.

The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.

Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.

Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.

These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.

A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.

The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.

Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.

The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.

The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.

Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.

Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.

These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.

A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.

Scientist in the lab

Credit: Darren Baker

After reviewing data from more than 134,000 patients, researchers at the US Food and Drug Administration (FDA) have concluded that dabigatran has a favorable risk-benefit profile.

Their research showed that, compared to warfarin, dabigatran decreased the risk of stroke, death, and intracranial hemorrhage in patients with atrial fibrillation.

On the other hand, dabigatran increased the risk of gastrointestinal bleeding, and the risk of myocardial infarction was similar for the 2 drugs.

This study was part of the FDA’s ongoing review of dabigatran. The agency has been investigating the safety of dabigatran since 2011, following reports of serious bleeding events associated with the drug.

A previous FDA study, announced in 2012, suggested dabigatran does not pose an increased risk of serious bleeding when compared to warfarin. But other studies have provided conflicting results, so the FDA decided to conduct additional research.

This study included information from more than 134,000 Medicare patients, aged 65 years or older. The researchers compared dabigatran and warfarin, evaluating the risk of ischemic stroke, intracranial hemorrhage, major gastrointestinal bleeding, myocardial infarction, and death.

The FDA said this study is based on a much larger and older patient population than those used in the agency’s earlier review of post-market data, and researchers employed a more sophisticated analytical method to capture and analyze the events of concern.

The data showed that, among new users of anticoagulants, dabigatran was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, when compared to warfarin.

The incidence rate of ischemic stroke per 1000 person-years was 11.3 among dabigatran users and 13.9 among warfarin users (hazard ratio [HR]=0.80).

The incidence of intracranial hemorrhage was 3.3 and 9.6, respectively (HR=0.34). And the incidence of death was 32.6 and 37.8, respectively (HR=0.86).

The study also showed an increased risk of major gastrointestinal bleeding with the use of dabigatran compared to warfarin. The incidence rate per 1000 person-years was 34.2 and 26.5, respectively (HR=1.28).

The risk of myocardial infarction was similar for the 2 drugs. The incidence rate per 1000 person-years was 15.7 for dabigatran users and 16.9 for warfarin users (HR=0.92).

These results, except with regard to myocardial infarction, are consistent with the clinical trial results that provided the basis for dabigatran’s approval.

The FDA said these findings suggest dabigatran has a favorable risk-benefit profile, so the agency has made no changes to the drug’s current label or recommendations for use.

The FDA is planning to publish detailed data from this study. Until then, some information is available on the agency’s website.

The FDA said it will continue to investigate the reasons for differences in major gastrointestinal bleeding rates for dabigatran and warfarin. And it will continue reviewing anticoagulant use and the risk of bleeding.

Scientist in the lab

Credit: Darren Baker

After reviewing data from more than 134,000 patients, researchers at the US Food and Drug Administration (FDA) have concluded that dabigatran has a favorable risk-benefit profile.

Their research showed that, compared to warfarin, dabigatran decreased the risk of stroke, death, and intracranial hemorrhage in patients with atrial fibrillation.

On the other hand, dabigatran increased the risk of gastrointestinal bleeding, and the risk of myocardial infarction was similar for the 2 drugs.

This study was part of the FDA’s ongoing review of dabigatran. The agency has been investigating the safety of dabigatran since 2011, following reports of serious bleeding events associated with the drug.

A previous FDA study, announced in 2012, suggested dabigatran does not pose an increased risk of serious bleeding when compared to warfarin. But other studies have provided conflicting results, so the FDA decided to conduct additional research.

This study included information from more than 134,000 Medicare patients, aged 65 years or older. The researchers compared dabigatran and warfarin, evaluating the risk of ischemic stroke, intracranial hemorrhage, major gastrointestinal bleeding, myocardial infarction, and death.

The FDA said this study is based on a much larger and older patient population than those used in the agency’s earlier review of post-market data, and researchers employed a more sophisticated analytical method to capture and analyze the events of concern.

The data showed that, among new users of anticoagulants, dabigatran was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, when compared to warfarin.

The incidence rate of ischemic stroke per 1000 person-years was 11.3 among dabigatran users and 13.9 among warfarin users (hazard ratio [HR]=0.80).

The incidence of intracranial hemorrhage was 3.3 and 9.6, respectively (HR=0.34). And the incidence of death was 32.6 and 37.8, respectively (HR=0.86).

The study also showed an increased risk of major gastrointestinal bleeding with the use of dabigatran compared to warfarin. The incidence rate per 1000 person-years was 34.2 and 26.5, respectively (HR=1.28).

The risk of myocardial infarction was similar for the 2 drugs. The incidence rate per 1000 person-years was 15.7 for dabigatran users and 16.9 for warfarin users (HR=0.92).

These results, except with regard to myocardial infarction, are consistent with the clinical trial results that provided the basis for dabigatran’s approval.

The FDA said these findings suggest dabigatran has a favorable risk-benefit profile, so the agency has made no changes to the drug’s current label or recommendations for use.

The FDA is planning to publish detailed data from this study. Until then, some information is available on the agency’s website.

The FDA said it will continue to investigate the reasons for differences in major gastrointestinal bleeding rates for dabigatran and warfarin. And it will continue reviewing anticoagulant use and the risk of bleeding.

Scientist in the lab

Credit: Darren Baker

After reviewing data from more than 134,000 patients, researchers at the US Food and Drug Administration (FDA) have concluded that dabigatran has a favorable risk-benefit profile.

Their research showed that, compared to warfarin, dabigatran decreased the risk of stroke, death, and intracranial hemorrhage in patients with atrial fibrillation.

On the other hand, dabigatran increased the risk of gastrointestinal bleeding, and the risk of myocardial infarction was similar for the 2 drugs.

This study was part of the FDA’s ongoing review of dabigatran. The agency has been investigating the safety of dabigatran since 2011, following reports of serious bleeding events associated with the drug.

A previous FDA study, announced in 2012, suggested dabigatran does not pose an increased risk of serious bleeding when compared to warfarin. But other studies have provided conflicting results, so the FDA decided to conduct additional research.

This study included information from more than 134,000 Medicare patients, aged 65 years or older. The researchers compared dabigatran and warfarin, evaluating the risk of ischemic stroke, intracranial hemorrhage, major gastrointestinal bleeding, myocardial infarction, and death.

The FDA said this study is based on a much larger and older patient population than those used in the agency’s earlier review of post-market data, and researchers employed a more sophisticated analytical method to capture and analyze the events of concern.

The data showed that, among new users of anticoagulants, dabigatran was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, when compared to warfarin.

The incidence rate of ischemic stroke per 1000 person-years was 11.3 among dabigatran users and 13.9 among warfarin users (hazard ratio [HR]=0.80).

The incidence of intracranial hemorrhage was 3.3 and 9.6, respectively (HR=0.34). And the incidence of death was 32.6 and 37.8, respectively (HR=0.86).

The study also showed an increased risk of major gastrointestinal bleeding with the use of dabigatran compared to warfarin. The incidence rate per 1000 person-years was 34.2 and 26.5, respectively (HR=1.28).

The risk of myocardial infarction was similar for the 2 drugs. The incidence rate per 1000 person-years was 15.7 for dabigatran users and 16.9 for warfarin users (HR=0.92).

These results, except with regard to myocardial infarction, are consistent with the clinical trial results that provided the basis for dabigatran’s approval.

The FDA said these findings suggest dabigatran has a favorable risk-benefit profile, so the agency has made no changes to the drug’s current label or recommendations for use.

The FDA is planning to publish detailed data from this study. Until then, some information is available on the agency’s website.

The FDA said it will continue to investigate the reasons for differences in major gastrointestinal bleeding rates for dabigatran and warfarin. And it will continue reviewing anticoagulant use and the risk of bleeding.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Warfarin tablets

Alere Inc., has initiated a Class 1 recall in the US of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2).

The strips are used by healthcare professionals to determine the international normalized ratio (INR) in fresh capillary whole blood to monitor the effect of warfarin on clotting time.

Alere has received reports of patients who had a therapeutic or near therapeutic INR with the test strips but a significantly higher INR in tests performed by a central lab.

This error has been linked to 9 reports of serious adverse events, 3 of which described bleeding associated with patient deaths.

So the company has issued a recall of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2). This recall does not include the Alere INRatio PT/INR Test Strip (PN 100071), which is used by patients for home INR monitoring.

Alere has not determined the root cause of the error but is concerned that the test strips may continue to report inaccurately low INR results. In the reports, the test strip results were between 3.1 and 12.2 INR units lower than the lab results.

Customers should stop using the Alere INRatio2 PT/INR Professional Test Strips immediately and return unused product to the company.

Alere will transition customers from the current Alere INRatio2 PT/INR Professional Test Strip to the Alere INRatio PT/INR Test Strip (PN 100139).

Alere said it has reported this issue to the US Food and Drug Administration and is conducting a thorough investigation into the adverse events.

Customers with questions about this recall and those who require replacement product can contact Alere at 844-292-5373. For additional information on the recall, visit www.inr-care.com.

Any adverse events or quality problems related to use of the test strips can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Warfarin tablets

Alere Inc., has initiated a Class 1 recall in the US of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2).

The strips are used by healthcare professionals to determine the international normalized ratio (INR) in fresh capillary whole blood to monitor the effect of warfarin on clotting time.

Alere has received reports of patients who had a therapeutic or near therapeutic INR with the test strips but a significantly higher INR in tests performed by a central lab.

This error has been linked to 9 reports of serious adverse events, 3 of which described bleeding associated with patient deaths.

So the company has issued a recall of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2). This recall does not include the Alere INRatio PT/INR Test Strip (PN 100071), which is used by patients for home INR monitoring.

Alere has not determined the root cause of the error but is concerned that the test strips may continue to report inaccurately low INR results. In the reports, the test strip results were between 3.1 and 12.2 INR units lower than the lab results.

Customers should stop using the Alere INRatio2 PT/INR Professional Test Strips immediately and return unused product to the company.

Alere will transition customers from the current Alere INRatio2 PT/INR Professional Test Strip to the Alere INRatio PT/INR Test Strip (PN 100139).

Alere said it has reported this issue to the US Food and Drug Administration and is conducting a thorough investigation into the adverse events.

Customers with questions about this recall and those who require replacement product can contact Alere at 844-292-5373. For additional information on the recall, visit www.inr-care.com.

Any adverse events or quality problems related to use of the test strips can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Warfarin tablets

Alere Inc., has initiated a Class 1 recall in the US of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2).

The strips are used by healthcare professionals to determine the international normalized ratio (INR) in fresh capillary whole blood to monitor the effect of warfarin on clotting time.

Alere has received reports of patients who had a therapeutic or near therapeutic INR with the test strips but a significantly higher INR in tests performed by a central lab.

This error has been linked to 9 reports of serious adverse events, 3 of which described bleeding associated with patient deaths.

So the company has issued a recall of the Alere INRatio2 PT/INR Professional Test Strips (PN 99008G2). This recall does not include the Alere INRatio PT/INR Test Strip (PN 100071), which is used by patients for home INR monitoring.

Alere has not determined the root cause of the error but is concerned that the test strips may continue to report inaccurately low INR results. In the reports, the test strip results were between 3.1 and 12.2 INR units lower than the lab results.

Customers should stop using the Alere INRatio2 PT/INR Professional Test Strips immediately and return unused product to the company.

Alere will transition customers from the current Alere INRatio2 PT/INR Professional Test Strip to the Alere INRatio PT/INR Test Strip (PN 100139).

Alere said it has reported this issue to the US Food and Drug Administration and is conducting a thorough investigation into the adverse events.

Customers with questions about this recall and those who require replacement product can contact Alere at 844-292-5373. For additional information on the recall, visit www.inr-care.com.

Any adverse events or quality problems related to use of the test strips can be reported to the FDA’s MedWatch Adverse Event Reporting Program.