Pharmacy

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.

Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.

Bortezomib retreatment may be started at the last dose the patient tolerated.

The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.

The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).

In this study, 94 of the patients received bortezomib in combination with dexamethasone.

One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).

The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.

The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.

Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.

The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.

Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.

Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.

Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.

Bortezomib retreatment may be started at the last dose the patient tolerated.

The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.

The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).

In this study, 94 of the patients received bortezomib in combination with dexamethasone.

One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).

The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.

The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.

Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.

The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.

Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.

Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.

Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.

Bortezomib retreatment may be started at the last dose the patient tolerated.

The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.

The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).

In this study, 94 of the patients received bortezomib in combination with dexamethasone.

One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).

The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.

The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.

Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.

The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.

Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.

Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.