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Flu and COVID-19 vaccines can be given on the same day: CDC and AAP
Previously, the CDC recommended that people receive their COVID-19 vaccinations alone and schedule any other vaccinations at least 2 weeks before or after their COVID-19 immunization. “This was out of an abundance of caution during a period when these vaccines were new and not due to any known safety or immunogenicity concerns,” the CDC guidance states. “However, substantial data have now been collected regarding the safety of COVID-19 vaccines currently approved or authorized by FDA.”
The guidance allowing for coadministration of COVID-19 vaccines with other immunizations, including the flu shot, was issued in mid-May 2021, and was restated in influenza vaccine recommendations released Aug. 27. The American Academy of Pediatrics soon followed suit, announcing that, for children eligible for the COVID-19 vaccine (age 12 and older), AAP recommendations allow for both the influenza and COVID-19 vaccines to be administered during the same visit.
Although there is limited data around giving COVID-19 vaccines with other vaccines, “extensive experience with non–COVID-19 vaccines has demonstrated that immunogenicity and adverse-event profiles are generally similar when vaccines are administered simultaneously as when they are administered alone,” the recommendations state. If administering other immunizations along with COVID-19 vaccines, providers should separate injection sites by at least 1 inch, the CDC recommends, and influenza vaccines that are more likely to cause a local reaction, like high-dose or the adjuvanted inactivated flu vaccine, should be administered in different limbs, if possible.
Whether someone should get their flu vaccine at the same time or separate from a COVID-19 vaccination or booster is a matter of personal preference as well as convenience, Susan Coffin, MD, MPH, an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, said in an interview. “It basically boils down to: Will you be able to get your flu shot without any difficulty in 2 weeks’ time?” she said. “We don’t want inconvenience or difficulties in access to get the way of people getting their flu shot this year.”
A version of this article first appeared on Medscape.com.
Previously, the CDC recommended that people receive their COVID-19 vaccinations alone and schedule any other vaccinations at least 2 weeks before or after their COVID-19 immunization. “This was out of an abundance of caution during a period when these vaccines were new and not due to any known safety or immunogenicity concerns,” the CDC guidance states. “However, substantial data have now been collected regarding the safety of COVID-19 vaccines currently approved or authorized by FDA.”
The guidance allowing for coadministration of COVID-19 vaccines with other immunizations, including the flu shot, was issued in mid-May 2021, and was restated in influenza vaccine recommendations released Aug. 27. The American Academy of Pediatrics soon followed suit, announcing that, for children eligible for the COVID-19 vaccine (age 12 and older), AAP recommendations allow for both the influenza and COVID-19 vaccines to be administered during the same visit.
Although there is limited data around giving COVID-19 vaccines with other vaccines, “extensive experience with non–COVID-19 vaccines has demonstrated that immunogenicity and adverse-event profiles are generally similar when vaccines are administered simultaneously as when they are administered alone,” the recommendations state. If administering other immunizations along with COVID-19 vaccines, providers should separate injection sites by at least 1 inch, the CDC recommends, and influenza vaccines that are more likely to cause a local reaction, like high-dose or the adjuvanted inactivated flu vaccine, should be administered in different limbs, if possible.
Whether someone should get their flu vaccine at the same time or separate from a COVID-19 vaccination or booster is a matter of personal preference as well as convenience, Susan Coffin, MD, MPH, an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, said in an interview. “It basically boils down to: Will you be able to get your flu shot without any difficulty in 2 weeks’ time?” she said. “We don’t want inconvenience or difficulties in access to get the way of people getting their flu shot this year.”
A version of this article first appeared on Medscape.com.
Previously, the CDC recommended that people receive their COVID-19 vaccinations alone and schedule any other vaccinations at least 2 weeks before or after their COVID-19 immunization. “This was out of an abundance of caution during a period when these vaccines were new and not due to any known safety or immunogenicity concerns,” the CDC guidance states. “However, substantial data have now been collected regarding the safety of COVID-19 vaccines currently approved or authorized by FDA.”
The guidance allowing for coadministration of COVID-19 vaccines with other immunizations, including the flu shot, was issued in mid-May 2021, and was restated in influenza vaccine recommendations released Aug. 27. The American Academy of Pediatrics soon followed suit, announcing that, for children eligible for the COVID-19 vaccine (age 12 and older), AAP recommendations allow for both the influenza and COVID-19 vaccines to be administered during the same visit.
Although there is limited data around giving COVID-19 vaccines with other vaccines, “extensive experience with non–COVID-19 vaccines has demonstrated that immunogenicity and adverse-event profiles are generally similar when vaccines are administered simultaneously as when they are administered alone,” the recommendations state. If administering other immunizations along with COVID-19 vaccines, providers should separate injection sites by at least 1 inch, the CDC recommends, and influenza vaccines that are more likely to cause a local reaction, like high-dose or the adjuvanted inactivated flu vaccine, should be administered in different limbs, if possible.
Whether someone should get their flu vaccine at the same time or separate from a COVID-19 vaccination or booster is a matter of personal preference as well as convenience, Susan Coffin, MD, MPH, an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, said in an interview. “It basically boils down to: Will you be able to get your flu shot without any difficulty in 2 weeks’ time?” she said. “We don’t want inconvenience or difficulties in access to get the way of people getting their flu shot this year.”
A version of this article first appeared on Medscape.com.
FDA moves to block some vape products, delays action on Juul
The agency had a court-ordered deadline of Sept. 9 to review more than 6.5 million applications for approval of what are considered new tobacco products – the vast majority of which are e-cigarettes and liquids, none of which have gone through FDA review before.
The FDA reviewed 93% of those applications in the past year, acting FDA Commissioner Janet Woodcock, MD, and Mitch Zeller, director of the FDA’s Center for Tobacco Products, said in a statement.
Of those reviewed, the agency rejected more than 946,000 flavored vape products, “because their applications lacked sufficient evidence that they have a benefit to adult smokers sufficient to overcome the public health threat posed by the well-documented, alarming levels of youth use of such products,” Dr. Woodcock and Mr. Zeller said.
The pair said more work is needed to finish the reviews to “ensure that we continue taking appropriate action to protect our nation’s youth from the dangers of all tobacco products, including e-cigarettes, which remain the most commonly used tobacco product by youth in the United States.”
No e-cigarette product has been given official FDA approval to be sold, meaning all e-cigarette products technically are on the market illegally, the agency said in 2020, but federal officials decided only to begin enforcing rules against flavored products, which surveys show are more often used by children. Tobacco-flavored and menthol e-cigarette products – which some adults use to quit smoking cigarettes – were exempted.
The American Cancer Society and other advocacy groups slammed the FDA’s decision to withhold action on major e-cigarette manufacturers, including Juul.
“The FDA’s failure today to act on applications by Juul, the manufacturer with the single biggest e-cigarette market share, is extremely disappointing and will allow the industry to further endanger public health and hook more kids on their highly addictive products,” Lisa Lacasse, president of ACS CAN, said in a statement, according to CNN.
“The FDA has had ample time to review the applications and allowing additional delays is unconscionable. There is overwhelming data to demonstrate the negative impact these kinds of flavored products have had on public health and their role in the youth e-cigarette epidemic. The time to act is now,” Ms. Lacasse added.
E-cigarette use among high school students rose from 11.7% in 2017 to 19.6% in 2020, the American Cancer Society said. Nearly 5% of middle schoolers reported using them in 2020.
A version of this article first appeared on WebMD.com.
The agency had a court-ordered deadline of Sept. 9 to review more than 6.5 million applications for approval of what are considered new tobacco products – the vast majority of which are e-cigarettes and liquids, none of which have gone through FDA review before.
The FDA reviewed 93% of those applications in the past year, acting FDA Commissioner Janet Woodcock, MD, and Mitch Zeller, director of the FDA’s Center for Tobacco Products, said in a statement.
Of those reviewed, the agency rejected more than 946,000 flavored vape products, “because their applications lacked sufficient evidence that they have a benefit to adult smokers sufficient to overcome the public health threat posed by the well-documented, alarming levels of youth use of such products,” Dr. Woodcock and Mr. Zeller said.
The pair said more work is needed to finish the reviews to “ensure that we continue taking appropriate action to protect our nation’s youth from the dangers of all tobacco products, including e-cigarettes, which remain the most commonly used tobacco product by youth in the United States.”
No e-cigarette product has been given official FDA approval to be sold, meaning all e-cigarette products technically are on the market illegally, the agency said in 2020, but federal officials decided only to begin enforcing rules against flavored products, which surveys show are more often used by children. Tobacco-flavored and menthol e-cigarette products – which some adults use to quit smoking cigarettes – were exempted.
The American Cancer Society and other advocacy groups slammed the FDA’s decision to withhold action on major e-cigarette manufacturers, including Juul.
“The FDA’s failure today to act on applications by Juul, the manufacturer with the single biggest e-cigarette market share, is extremely disappointing and will allow the industry to further endanger public health and hook more kids on their highly addictive products,” Lisa Lacasse, president of ACS CAN, said in a statement, according to CNN.
“The FDA has had ample time to review the applications and allowing additional delays is unconscionable. There is overwhelming data to demonstrate the negative impact these kinds of flavored products have had on public health and their role in the youth e-cigarette epidemic. The time to act is now,” Ms. Lacasse added.
E-cigarette use among high school students rose from 11.7% in 2017 to 19.6% in 2020, the American Cancer Society said. Nearly 5% of middle schoolers reported using them in 2020.
A version of this article first appeared on WebMD.com.
The agency had a court-ordered deadline of Sept. 9 to review more than 6.5 million applications for approval of what are considered new tobacco products – the vast majority of which are e-cigarettes and liquids, none of which have gone through FDA review before.
The FDA reviewed 93% of those applications in the past year, acting FDA Commissioner Janet Woodcock, MD, and Mitch Zeller, director of the FDA’s Center for Tobacco Products, said in a statement.
Of those reviewed, the agency rejected more than 946,000 flavored vape products, “because their applications lacked sufficient evidence that they have a benefit to adult smokers sufficient to overcome the public health threat posed by the well-documented, alarming levels of youth use of such products,” Dr. Woodcock and Mr. Zeller said.
The pair said more work is needed to finish the reviews to “ensure that we continue taking appropriate action to protect our nation’s youth from the dangers of all tobacco products, including e-cigarettes, which remain the most commonly used tobacco product by youth in the United States.”
No e-cigarette product has been given official FDA approval to be sold, meaning all e-cigarette products technically are on the market illegally, the agency said in 2020, but federal officials decided only to begin enforcing rules against flavored products, which surveys show are more often used by children. Tobacco-flavored and menthol e-cigarette products – which some adults use to quit smoking cigarettes – were exempted.
The American Cancer Society and other advocacy groups slammed the FDA’s decision to withhold action on major e-cigarette manufacturers, including Juul.
“The FDA’s failure today to act on applications by Juul, the manufacturer with the single biggest e-cigarette market share, is extremely disappointing and will allow the industry to further endanger public health and hook more kids on their highly addictive products,” Lisa Lacasse, president of ACS CAN, said in a statement, according to CNN.
“The FDA has had ample time to review the applications and allowing additional delays is unconscionable. There is overwhelming data to demonstrate the negative impact these kinds of flavored products have had on public health and their role in the youth e-cigarette epidemic. The time to act is now,” Ms. Lacasse added.
E-cigarette use among high school students rose from 11.7% in 2017 to 19.6% in 2020, the American Cancer Society said. Nearly 5% of middle schoolers reported using them in 2020.
A version of this article first appeared on WebMD.com.
FDA inaction on hair loss drug’s suicide, depression, erectile dysfunction risk sparks lawsuit
Consumer advocacy group 4 years ago.
The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation.
As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.
Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.
The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.
“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.
Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.
“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.
The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online.
This news organization reached out to the FDA for comment but did not receive a response by press time.
A version of this article first appeared on Medscape.com.
Consumer advocacy group 4 years ago.
The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation.
As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.
Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.
The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.
“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.
Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.
“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.
The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online.
This news organization reached out to the FDA for comment but did not receive a response by press time.
A version of this article first appeared on Medscape.com.
Consumer advocacy group 4 years ago.
The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation.
As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.
Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.
The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.
“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.
Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.
“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.
The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online.
This news organization reached out to the FDA for comment but did not receive a response by press time.
A version of this article first appeared on Medscape.com.
FDA approves zanubrutinib in Waldenström’s macroglobulinemia
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
Three JAK inhibitors get boxed warnings, modified indications
The arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR) poses an increased risk of serious cardiac events such as heart attack or stroke, cancer, blood clots, and death, the Food and Drug Administration announced Sept 1.
Manufacturers of this drug along with other Janus kinase (JAK) inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) must update their boxed warnings to include information about these health risks. The FDA made the determination after new study data from Pfizer, which manufacturers Xeljanz, found an association between a lower dose of Xeljanz and increased risk of blood clots and death.
“Recommendations for healthcare professionals will include consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy,” the agency stated.
The FDA is limiting all approved uses of these three medications to patients who have not responded well to tumor necrosis factor (TNF) blockers to ensure their benefits outweigh their risks. Tofacitinib is indicated for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA. The FDA included baricitinib and upadacitinib in the warning because of the similar properties they share with tofacitinib, even though they haven’t been studied as extensively.
“We believe this update will bring important clarity for healthcare plans on the risk/benefit profile of Xeljanz, which is a medicine informed by more clinical data than any other JAK inhibitor,” Pfizer said in a statement.
Investigators for the ORAL Surveillance trial compared two doses of tofacitinib (5 mg twice daily and 10 mg twice daily) with TNF blockers in patients with rheumatoid arthritis who were aged 50 years or older with at least one additional cardiovascular risk factor.
For both dose regimens of tofacitinib, they found an increased risk of major adverse cardiovascular events, malignancies, thrombosis, and death compared with the TNF blocker regimen. In addition, rates of lung cancers and lymphomas were higher with tofacitinib. In trial data released earlier this year, Pfizer revealed that the tofacitinib group had a much higher incidence of adjudicated malignancies compared with the TNF blocker group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09).
Impact on clinical practice
Physicians treating patients who have rheumatoid arthritis with tofacitinib may initially decrease prescriptions following the FDA’s drug safety communication, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy) – particularly those with a principal mechanism of action slightly different from that of tofacitinib, he added.
“Tofacitinib is principally a JAK 1,3 inhibitor at usual concentrations, whereas upadacitinib and baricitinib are JAK 1,2 inhibitors. Thus, I speculate that the tofacitinib prescriptions will go down more than the upadacitinib and baricitinib prescriptions,” he said in an interview.
Some patients may also be worried about taking tofacitinib, particularly those with previous events or predisposing conditions, Dr. Furst noted.
“First and foremost, I think we need to actually look at the data in a publication rather than just an FDA statement before making huge changes in our practice,” he advised.
“I am looking forward to the data finally being published ... It’s interesting that the full data still isn’t really out there beyond the press releases and an abstract. I think there’s a lot more to learn about how these drugs work and who is really at risk for harmful events,” said Alexis R. Ogdie, MD, MSCE, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
Pfizer’s data also may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
“I think many rheumatologists have already taken this information in, and begun to incorporate it into their discussions with their patients” since it has been over a year since the first public release of information about the ORAL Surveillance trial, said Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego. “I don’t know that it will affect the approvals, but it will impact their labels.”
Wariness to prescribing tofacitinib may be lower for patients younger than those in the ORAL Surveillance trial without additional cardiovascular risk factors who are taking tofacitinib for non-RA indications, said gastroenterologist Miguel Regueiro, MD.
“The JAK inhibitor warning by the FDA is an important consideration for any prescriber or patient. The risk of cardiovascular disease and venous thromboembolism with this class of medicine appears higher in older rheumatoid arthritis patients with underlying cardiovascular disease. While the warning applies to all JAK inhibitors and likely the newer selective JAK inhibitors to come, we need to weigh the risk and benefit based on the indication for prescribing,” said Dr. Regueiro, chair of the Digestive Disease and Surgery Institute and of the department of gastroenterology, hepatology and nutrition at the Cleveland Clinic in Ohio.
“I do think that there will be a heightened awareness and wariness for older RA patients and for the prescribers. However, for inflammatory bowel disease (and other non-RA indications), it does not appear that the risk for cardiovascular disease and VTE are significantly increased. To that end, in my own practice, I still use tofacitinib for ulcerative colitis and will do the same for the selective JAK inhibitors to come for IBD. Of course, as with any medication, we need to have discussions with our patients, alert them to potential side effects and have an open line of communication for any questions or concerns.”
Gastroenterologist Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, thought that while patients with RA have many other treatment options besides JAK inhibitors, fewer options available to patients with IBD “may motivate the use of oral [sphingosine-1-phosphate receptor modulator] agents such as ozanimod, although IBD patients are younger and [have fewer] MACE risk factors than RA patients, so absolute risk is very small in the ulcerative colitis population.”
Pfizer’s data may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
The agency’s decision corroborates an earlier 2019 warning about the increased risk of blood clots and of death in patients with ulcerative colitis taking 10 mg tofacitinib twice daily.
The FDA said that two other JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic), are not indicated for the treatment of arthritis and other inflammatory conditions, and so are not a part of the updates being required.
Baricitinib, abrocitinib, and upadacitinib are currently under FDA review for treating atopic dermatitis (AD); a topical formulation of the JAK1/2 inhibitor ruxolitinib is under review for treating AD. Reviews for all 4 have been extended. In September 2020, baricitinib was approved for treating moderate to severe AD in Europe, at a dose of 4 mg once a day, with recommendations that the dose can be reduced to 2 mg once a day when the disease is under control, and that the dose may need to be reduced in patients with impaired kidney function, those with an increased risk of infections, and those older than aged 75 years.
In an interview, Jacob Thyssen, MD, PhD, professor of dermatology at the University of Copenhagen, said that in the EU, there has been “extensive education” about cardiovascular risks with baricitinib “and it is my impression that payers and dermatologists in Europe are confident that it is safe to use in AD.” In addition, there has been an emphasis on the differences in cardiovascular risk factors between RA and AD patients, “given that the latter group is generally young and lean.” In the United States, he added, it will be interesting to see which doses of the JAK inhibitors will be approved for AD.
Dr. Thyssen disclosed that he is a speaker, advisory board member and/or investigator for Regeneron, Sanofi-Genzyme, Eli Lilly, Pfizer, LEO Pharma, AbbVie, and Almirall.
*This story was updated 9/3/21 and 9/6/2021.
A version of this article first appeared on Medscape.com.
The arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR) poses an increased risk of serious cardiac events such as heart attack or stroke, cancer, blood clots, and death, the Food and Drug Administration announced Sept 1.
Manufacturers of this drug along with other Janus kinase (JAK) inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) must update their boxed warnings to include information about these health risks. The FDA made the determination after new study data from Pfizer, which manufacturers Xeljanz, found an association between a lower dose of Xeljanz and increased risk of blood clots and death.
“Recommendations for healthcare professionals will include consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy,” the agency stated.
The FDA is limiting all approved uses of these three medications to patients who have not responded well to tumor necrosis factor (TNF) blockers to ensure their benefits outweigh their risks. Tofacitinib is indicated for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA. The FDA included baricitinib and upadacitinib in the warning because of the similar properties they share with tofacitinib, even though they haven’t been studied as extensively.
“We believe this update will bring important clarity for healthcare plans on the risk/benefit profile of Xeljanz, which is a medicine informed by more clinical data than any other JAK inhibitor,” Pfizer said in a statement.
Investigators for the ORAL Surveillance trial compared two doses of tofacitinib (5 mg twice daily and 10 mg twice daily) with TNF blockers in patients with rheumatoid arthritis who were aged 50 years or older with at least one additional cardiovascular risk factor.
For both dose regimens of tofacitinib, they found an increased risk of major adverse cardiovascular events, malignancies, thrombosis, and death compared with the TNF blocker regimen. In addition, rates of lung cancers and lymphomas were higher with tofacitinib. In trial data released earlier this year, Pfizer revealed that the tofacitinib group had a much higher incidence of adjudicated malignancies compared with the TNF blocker group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09).
Impact on clinical practice
Physicians treating patients who have rheumatoid arthritis with tofacitinib may initially decrease prescriptions following the FDA’s drug safety communication, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy) – particularly those with a principal mechanism of action slightly different from that of tofacitinib, he added.
“Tofacitinib is principally a JAK 1,3 inhibitor at usual concentrations, whereas upadacitinib and baricitinib are JAK 1,2 inhibitors. Thus, I speculate that the tofacitinib prescriptions will go down more than the upadacitinib and baricitinib prescriptions,” he said in an interview.
Some patients may also be worried about taking tofacitinib, particularly those with previous events or predisposing conditions, Dr. Furst noted.
“First and foremost, I think we need to actually look at the data in a publication rather than just an FDA statement before making huge changes in our practice,” he advised.
“I am looking forward to the data finally being published ... It’s interesting that the full data still isn’t really out there beyond the press releases and an abstract. I think there’s a lot more to learn about how these drugs work and who is really at risk for harmful events,” said Alexis R. Ogdie, MD, MSCE, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
Pfizer’s data also may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
“I think many rheumatologists have already taken this information in, and begun to incorporate it into their discussions with their patients” since it has been over a year since the first public release of information about the ORAL Surveillance trial, said Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego. “I don’t know that it will affect the approvals, but it will impact their labels.”
Wariness to prescribing tofacitinib may be lower for patients younger than those in the ORAL Surveillance trial without additional cardiovascular risk factors who are taking tofacitinib for non-RA indications, said gastroenterologist Miguel Regueiro, MD.
“The JAK inhibitor warning by the FDA is an important consideration for any prescriber or patient. The risk of cardiovascular disease and venous thromboembolism with this class of medicine appears higher in older rheumatoid arthritis patients with underlying cardiovascular disease. While the warning applies to all JAK inhibitors and likely the newer selective JAK inhibitors to come, we need to weigh the risk and benefit based on the indication for prescribing,” said Dr. Regueiro, chair of the Digestive Disease and Surgery Institute and of the department of gastroenterology, hepatology and nutrition at the Cleveland Clinic in Ohio.
“I do think that there will be a heightened awareness and wariness for older RA patients and for the prescribers. However, for inflammatory bowel disease (and other non-RA indications), it does not appear that the risk for cardiovascular disease and VTE are significantly increased. To that end, in my own practice, I still use tofacitinib for ulcerative colitis and will do the same for the selective JAK inhibitors to come for IBD. Of course, as with any medication, we need to have discussions with our patients, alert them to potential side effects and have an open line of communication for any questions or concerns.”
Gastroenterologist Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, thought that while patients with RA have many other treatment options besides JAK inhibitors, fewer options available to patients with IBD “may motivate the use of oral [sphingosine-1-phosphate receptor modulator] agents such as ozanimod, although IBD patients are younger and [have fewer] MACE risk factors than RA patients, so absolute risk is very small in the ulcerative colitis population.”
Pfizer’s data may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
The agency’s decision corroborates an earlier 2019 warning about the increased risk of blood clots and of death in patients with ulcerative colitis taking 10 mg tofacitinib twice daily.
The FDA said that two other JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic), are not indicated for the treatment of arthritis and other inflammatory conditions, and so are not a part of the updates being required.
Baricitinib, abrocitinib, and upadacitinib are currently under FDA review for treating atopic dermatitis (AD); a topical formulation of the JAK1/2 inhibitor ruxolitinib is under review for treating AD. Reviews for all 4 have been extended. In September 2020, baricitinib was approved for treating moderate to severe AD in Europe, at a dose of 4 mg once a day, with recommendations that the dose can be reduced to 2 mg once a day when the disease is under control, and that the dose may need to be reduced in patients with impaired kidney function, those with an increased risk of infections, and those older than aged 75 years.
In an interview, Jacob Thyssen, MD, PhD, professor of dermatology at the University of Copenhagen, said that in the EU, there has been “extensive education” about cardiovascular risks with baricitinib “and it is my impression that payers and dermatologists in Europe are confident that it is safe to use in AD.” In addition, there has been an emphasis on the differences in cardiovascular risk factors between RA and AD patients, “given that the latter group is generally young and lean.” In the United States, he added, it will be interesting to see which doses of the JAK inhibitors will be approved for AD.
Dr. Thyssen disclosed that he is a speaker, advisory board member and/or investigator for Regeneron, Sanofi-Genzyme, Eli Lilly, Pfizer, LEO Pharma, AbbVie, and Almirall.
*This story was updated 9/3/21 and 9/6/2021.
A version of this article first appeared on Medscape.com.
The arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR) poses an increased risk of serious cardiac events such as heart attack or stroke, cancer, blood clots, and death, the Food and Drug Administration announced Sept 1.
Manufacturers of this drug along with other Janus kinase (JAK) inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) must update their boxed warnings to include information about these health risks. The FDA made the determination after new study data from Pfizer, which manufacturers Xeljanz, found an association between a lower dose of Xeljanz and increased risk of blood clots and death.
“Recommendations for healthcare professionals will include consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy,” the agency stated.
The FDA is limiting all approved uses of these three medications to patients who have not responded well to tumor necrosis factor (TNF) blockers to ensure their benefits outweigh their risks. Tofacitinib is indicated for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA. The FDA included baricitinib and upadacitinib in the warning because of the similar properties they share with tofacitinib, even though they haven’t been studied as extensively.
“We believe this update will bring important clarity for healthcare plans on the risk/benefit profile of Xeljanz, which is a medicine informed by more clinical data than any other JAK inhibitor,” Pfizer said in a statement.
Investigators for the ORAL Surveillance trial compared two doses of tofacitinib (5 mg twice daily and 10 mg twice daily) with TNF blockers in patients with rheumatoid arthritis who were aged 50 years or older with at least one additional cardiovascular risk factor.
For both dose regimens of tofacitinib, they found an increased risk of major adverse cardiovascular events, malignancies, thrombosis, and death compared with the TNF blocker regimen. In addition, rates of lung cancers and lymphomas were higher with tofacitinib. In trial data released earlier this year, Pfizer revealed that the tofacitinib group had a much higher incidence of adjudicated malignancies compared with the TNF blocker group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09).
Impact on clinical practice
Physicians treating patients who have rheumatoid arthritis with tofacitinib may initially decrease prescriptions following the FDA’s drug safety communication, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy) – particularly those with a principal mechanism of action slightly different from that of tofacitinib, he added.
“Tofacitinib is principally a JAK 1,3 inhibitor at usual concentrations, whereas upadacitinib and baricitinib are JAK 1,2 inhibitors. Thus, I speculate that the tofacitinib prescriptions will go down more than the upadacitinib and baricitinib prescriptions,” he said in an interview.
Some patients may also be worried about taking tofacitinib, particularly those with previous events or predisposing conditions, Dr. Furst noted.
“First and foremost, I think we need to actually look at the data in a publication rather than just an FDA statement before making huge changes in our practice,” he advised.
“I am looking forward to the data finally being published ... It’s interesting that the full data still isn’t really out there beyond the press releases and an abstract. I think there’s a lot more to learn about how these drugs work and who is really at risk for harmful events,” said Alexis R. Ogdie, MD, MSCE, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
Pfizer’s data also may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
“I think many rheumatologists have already taken this information in, and begun to incorporate it into their discussions with their patients” since it has been over a year since the first public release of information about the ORAL Surveillance trial, said Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego. “I don’t know that it will affect the approvals, but it will impact their labels.”
Wariness to prescribing tofacitinib may be lower for patients younger than those in the ORAL Surveillance trial without additional cardiovascular risk factors who are taking tofacitinib for non-RA indications, said gastroenterologist Miguel Regueiro, MD.
“The JAK inhibitor warning by the FDA is an important consideration for any prescriber or patient. The risk of cardiovascular disease and venous thromboembolism with this class of medicine appears higher in older rheumatoid arthritis patients with underlying cardiovascular disease. While the warning applies to all JAK inhibitors and likely the newer selective JAK inhibitors to come, we need to weigh the risk and benefit based on the indication for prescribing,” said Dr. Regueiro, chair of the Digestive Disease and Surgery Institute and of the department of gastroenterology, hepatology and nutrition at the Cleveland Clinic in Ohio.
“I do think that there will be a heightened awareness and wariness for older RA patients and for the prescribers. However, for inflammatory bowel disease (and other non-RA indications), it does not appear that the risk for cardiovascular disease and VTE are significantly increased. To that end, in my own practice, I still use tofacitinib for ulcerative colitis and will do the same for the selective JAK inhibitors to come for IBD. Of course, as with any medication, we need to have discussions with our patients, alert them to potential side effects and have an open line of communication for any questions or concerns.”
Gastroenterologist Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, thought that while patients with RA have many other treatment options besides JAK inhibitors, fewer options available to patients with IBD “may motivate the use of oral [sphingosine-1-phosphate receptor modulator] agents such as ozanimod, although IBD patients are younger and [have fewer] MACE risk factors than RA patients, so absolute risk is very small in the ulcerative colitis population.”
Pfizer’s data may be affecting FDA approvals of other JAK inhibitors. This past summer, AbbVie and Eli Lilly stated that the FDA’s ongoing assessment of the safety trial was delaying the agency’s decisions about expanding use of their respective drugs upadacitinib and baricitinib.
The agency’s decision corroborates an earlier 2019 warning about the increased risk of blood clots and of death in patients with ulcerative colitis taking 10 mg tofacitinib twice daily.
The FDA said that two other JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic), are not indicated for the treatment of arthritis and other inflammatory conditions, and so are not a part of the updates being required.
Baricitinib, abrocitinib, and upadacitinib are currently under FDA review for treating atopic dermatitis (AD); a topical formulation of the JAK1/2 inhibitor ruxolitinib is under review for treating AD. Reviews for all 4 have been extended. In September 2020, baricitinib was approved for treating moderate to severe AD in Europe, at a dose of 4 mg once a day, with recommendations that the dose can be reduced to 2 mg once a day when the disease is under control, and that the dose may need to be reduced in patients with impaired kidney function, those with an increased risk of infections, and those older than aged 75 years.
In an interview, Jacob Thyssen, MD, PhD, professor of dermatology at the University of Copenhagen, said that in the EU, there has been “extensive education” about cardiovascular risks with baricitinib “and it is my impression that payers and dermatologists in Europe are confident that it is safe to use in AD.” In addition, there has been an emphasis on the differences in cardiovascular risk factors between RA and AD patients, “given that the latter group is generally young and lean.” In the United States, he added, it will be interesting to see which doses of the JAK inhibitors will be approved for AD.
Dr. Thyssen disclosed that he is a speaker, advisory board member and/or investigator for Regeneron, Sanofi-Genzyme, Eli Lilly, Pfizer, LEO Pharma, AbbVie, and Almirall.
*This story was updated 9/3/21 and 9/6/2021.
A version of this article first appeared on Medscape.com.
FDA approves first twice-yearly antipsychotic for schizophrenia
The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.
This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.
The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.
“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.
Noninferiority results
In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.
Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.
The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.
The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).
Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.
, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.
Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.
“Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.
“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.
This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.
The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.
“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.
Noninferiority results
In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.
Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.
The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.
The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).
Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.
, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.
Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.
“Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.
“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.
This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.
The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.
“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.
Noninferiority results
In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.
Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.
The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.
The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).
Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.
, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.
Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.
“Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.
“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.
A version of this article first appeared on Medscape.com.
FDA OKs IV Briviact for seizures in kids as young as 1 month
All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.
The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.
In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.
“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.
“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
Safety profile
Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”
The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.
In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.
Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.
Patients should be advised to report these symptoms immediately to a health care professional, the company noted.
A version of this article first appeared on Medscape.com.
All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.
The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.
In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.
“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.
“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
Safety profile
Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”
The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.
In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.
Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.
Patients should be advised to report these symptoms immediately to a health care professional, the company noted.
A version of this article first appeared on Medscape.com.
All three brivaracetam formulations (tablets, oral solution, and IV) may now be used. The approval marks the first time that the IV formulation will be available for children, the company said in a news release.
The medication is already approved in the United States as monotherapy and adjunctive therapy in adults with epilepsy.
In an open-label follow-up pediatric study, an estimated 71.4% of patients aged 1 month to 17 years with partial-onset seizures remained on brivaracetam therapy at 1 year, and 64.3% did so at 2 years, the company reported.
“We often see children with seizures hospitalized, so it’s important to have a therapy like Briviact IV that can offer rapid administration in an effective dose when needed and does not require titration,” Raman Sankar, MD, PhD, distinguished professor and chief of pediatric neurology, University of California, Los Angeles, said in the release.
“The availability of the oral dose forms also allows continuity of treatment when these young patients are transitioning from hospital to home,” he added.
Safety profile
Dr. Sankar noted that with approval now of both the IV and oral formulations for partial-onset seizures in such young children, “we have a new option that helps meet a critical need in pediatric epilepsy.”
The most common adverse reactions with brivaracetam include somnolence and sedation, dizziness, fatigue, nausea, and vomiting. In the pediatric clinical trials, the safety profile for pediatric patients was similar to adults.
In the adult trials, psychiatric adverse reactions, including nonpsychotic and psychotic symptoms, were reported in approximately 13% of adults taking at least 50 mg/day of brivaracetam compared with 8% taking placebo.
Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults.
Patients should be advised to report these symptoms immediately to a health care professional, the company noted.
A version of this article first appeared on Medscape.com.
FDA okays difelikefalin for dialysis-associated pruritus in patients with CKD
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Bimekizumab approved in Europe for psoriasis treatment
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
Empagliflozin gets HFrEF approval from FDA
The U.S. Food and Drug Administration approved empagliflozin (Jardiance) as a treatment for adults with heart failure with reduced ejection fraction (HFrEF) regardless of whether patients have diabetes on Aug. 18, making it the second agent from the sodium-glucose transporter 2 inhibitor class to received this indication.
Empagliflozin first received FDA marketing approval in 2014 for improving glycemic control in patients with type 2 diabetes, and in 2016 the agency added a second indication of reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease. The newly granted indication for patients with HFrEF without regard to glycemic status was for reducing the risk for cardiovascular death and hospitalization for heart failure, according to a statement from Boehringer Ingelheim and Lilly, the two companies that together market empagliflozin.
The statement also said that the approval allowed for empagliflozin treatment in patients with HFrEF and an estimated glomerular filtration rate (eGFR) as low as 20 mL/min per 1.73 m2, in contrast to its indication for improving glycemic control in patients with type 2 diabetes that limits use to patients with an eGFR of at least 30 mL per 1.73 m2.
EMPEROR-Reduced results drive approval
The FDA based its decision on results from the EMPEROR-Reduced study, first reported in August 2020, that showed treatment of patients with HFrEF with empagliflozin on top of standard therapy for a median of 16 months cut the incidence of cardiovascular death or hospitalization for worsening heart failure by 25% relative to placebo, and by an absolute 5.3%, compared with placebo-treated patients.
Patients enrolled in EMPEROR-Reduced had chronic heart failure in New York Heart Association functional class II-IV and with a left ventricular ejection fraction of 40% or less, the standard ejection fraction criterion for defining HFrEF. Half the enrolled patients had diabetes, and analysis showed no heterogeneity in the primary outcome response based on diabetes status at enrollment.
Empagliflozin joins dapagliflozin for treating HFrEF
Dapagliflozin (Farxiga) was the first agent from the SGLT2 inhibitor class to receive an FDA indication, in 2020, for treating patients with HFrEF regardless of their diabetes status, a decision based on results from the DAPA-HF trial. Results from DAPA-HF showed that treatment with dapagliflozin in patients with HFrEF for a median of 18 months led to a 26% relative reduction in the incidence of cardiovascular death or worsening heart failure and a 4.9% absolute reduction, compared with placebo when added to standard treatment. DAPA-HF enrolled patients using similar criteria to EMPEROR-Reduced, and 42% of enrolled patients had diabetes with no heterogeneity in the primary outcome related to baseline diabetes status.
Subsequent to the report of results from the EMPEROR-Reduced trial nearly a year ago, heart failure experts declared that treatment with an agent from the SGLT2 inhibitor class had become a “new pillar of foundational therapy for HFrEF,” and they urged rapid initiation of an SGLT2 inhibitor (along with other appropriate medications) at the time of initial diagnosis of HFrEF.
The U.S. Food and Drug Administration approved empagliflozin (Jardiance) as a treatment for adults with heart failure with reduced ejection fraction (HFrEF) regardless of whether patients have diabetes on Aug. 18, making it the second agent from the sodium-glucose transporter 2 inhibitor class to received this indication.
Empagliflozin first received FDA marketing approval in 2014 for improving glycemic control in patients with type 2 diabetes, and in 2016 the agency added a second indication of reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease. The newly granted indication for patients with HFrEF without regard to glycemic status was for reducing the risk for cardiovascular death and hospitalization for heart failure, according to a statement from Boehringer Ingelheim and Lilly, the two companies that together market empagliflozin.
The statement also said that the approval allowed for empagliflozin treatment in patients with HFrEF and an estimated glomerular filtration rate (eGFR) as low as 20 mL/min per 1.73 m2, in contrast to its indication for improving glycemic control in patients with type 2 diabetes that limits use to patients with an eGFR of at least 30 mL per 1.73 m2.
EMPEROR-Reduced results drive approval
The FDA based its decision on results from the EMPEROR-Reduced study, first reported in August 2020, that showed treatment of patients with HFrEF with empagliflozin on top of standard therapy for a median of 16 months cut the incidence of cardiovascular death or hospitalization for worsening heart failure by 25% relative to placebo, and by an absolute 5.3%, compared with placebo-treated patients.
Patients enrolled in EMPEROR-Reduced had chronic heart failure in New York Heart Association functional class II-IV and with a left ventricular ejection fraction of 40% or less, the standard ejection fraction criterion for defining HFrEF. Half the enrolled patients had diabetes, and analysis showed no heterogeneity in the primary outcome response based on diabetes status at enrollment.
Empagliflozin joins dapagliflozin for treating HFrEF
Dapagliflozin (Farxiga) was the first agent from the SGLT2 inhibitor class to receive an FDA indication, in 2020, for treating patients with HFrEF regardless of their diabetes status, a decision based on results from the DAPA-HF trial. Results from DAPA-HF showed that treatment with dapagliflozin in patients with HFrEF for a median of 18 months led to a 26% relative reduction in the incidence of cardiovascular death or worsening heart failure and a 4.9% absolute reduction, compared with placebo when added to standard treatment. DAPA-HF enrolled patients using similar criteria to EMPEROR-Reduced, and 42% of enrolled patients had diabetes with no heterogeneity in the primary outcome related to baseline diabetes status.
Subsequent to the report of results from the EMPEROR-Reduced trial nearly a year ago, heart failure experts declared that treatment with an agent from the SGLT2 inhibitor class had become a “new pillar of foundational therapy for HFrEF,” and they urged rapid initiation of an SGLT2 inhibitor (along with other appropriate medications) at the time of initial diagnosis of HFrEF.
The U.S. Food and Drug Administration approved empagliflozin (Jardiance) as a treatment for adults with heart failure with reduced ejection fraction (HFrEF) regardless of whether patients have diabetes on Aug. 18, making it the second agent from the sodium-glucose transporter 2 inhibitor class to received this indication.
Empagliflozin first received FDA marketing approval in 2014 for improving glycemic control in patients with type 2 diabetes, and in 2016 the agency added a second indication of reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease. The newly granted indication for patients with HFrEF without regard to glycemic status was for reducing the risk for cardiovascular death and hospitalization for heart failure, according to a statement from Boehringer Ingelheim and Lilly, the two companies that together market empagliflozin.
The statement also said that the approval allowed for empagliflozin treatment in patients with HFrEF and an estimated glomerular filtration rate (eGFR) as low as 20 mL/min per 1.73 m2, in contrast to its indication for improving glycemic control in patients with type 2 diabetes that limits use to patients with an eGFR of at least 30 mL per 1.73 m2.
EMPEROR-Reduced results drive approval
The FDA based its decision on results from the EMPEROR-Reduced study, first reported in August 2020, that showed treatment of patients with HFrEF with empagliflozin on top of standard therapy for a median of 16 months cut the incidence of cardiovascular death or hospitalization for worsening heart failure by 25% relative to placebo, and by an absolute 5.3%, compared with placebo-treated patients.
Patients enrolled in EMPEROR-Reduced had chronic heart failure in New York Heart Association functional class II-IV and with a left ventricular ejection fraction of 40% or less, the standard ejection fraction criterion for defining HFrEF. Half the enrolled patients had diabetes, and analysis showed no heterogeneity in the primary outcome response based on diabetes status at enrollment.
Empagliflozin joins dapagliflozin for treating HFrEF
Dapagliflozin (Farxiga) was the first agent from the SGLT2 inhibitor class to receive an FDA indication, in 2020, for treating patients with HFrEF regardless of their diabetes status, a decision based on results from the DAPA-HF trial. Results from DAPA-HF showed that treatment with dapagliflozin in patients with HFrEF for a median of 18 months led to a 26% relative reduction in the incidence of cardiovascular death or worsening heart failure and a 4.9% absolute reduction, compared with placebo when added to standard treatment. DAPA-HF enrolled patients using similar criteria to EMPEROR-Reduced, and 42% of enrolled patients had diabetes with no heterogeneity in the primary outcome related to baseline diabetes status.
Subsequent to the report of results from the EMPEROR-Reduced trial nearly a year ago, heart failure experts declared that treatment with an agent from the SGLT2 inhibitor class had become a “new pillar of foundational therapy for HFrEF,” and they urged rapid initiation of an SGLT2 inhibitor (along with other appropriate medications) at the time of initial diagnosis of HFrEF.