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FDA approves combo pill for severe, acute pain
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
Donafenib shows potential as first-line treatment of advanced hepatocellular carcinoma
“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.
Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.
This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority.
Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”
Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.
“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”
Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.
“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.
Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.
This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority.
Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”
Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.
“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”
Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.
“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.
Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.
This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority.
Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”
Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.
“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”
Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Tramadol linked to higher risk of mortality, compared with codeine
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
FDA OKs new high-dose naloxone product for opioid overdose
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
FDA approves cell-based flu shot for ages 6 months and older
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
Few JAK inhibitor users have diminished immune response to COVID-19 vaccines
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
FROM THE LANCET RHEUMATOLOGY
Adalimumab biosimilar Cyltezo gets interchangeability designation
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
Lupin recalls irbesartan and hydrochlorothiazide/irbesartan tablets
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
New antimigraine drugs linked with less risk for adverse events
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
FROM JAMA NETWORK OPEN
Rivaroxaban’s single daily dose may lead to higher bleeding risk than other DOACs
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
FROM ANNALS OF INTERNAL MEDICINE