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*Only for medical professionals to read for reference.
Digging deep into safety issues is the foundation of medication safety
.
As the understanding of the mechanism of rheumatism continues to deepen, relevant targeted drugs continue to be developed and innovated
.
In the process of innovation and application of drugs such as biological agents and small molecules, the safety and effectiveness of drugs also urgently need to be determined
.
At the just-concluded 2021 American College of Rheumatology (ACR) Annual Meeting (ACR 2021), Dr.
Anil Rajpal, head of the Rheumatology and Transplant Medicine Group of the U.
S.
Food and Drug Administration (FDA) The topic of "the latest news of the issue" was shared
.
In this issue, Wang Yuhua, director of the Department of Rheumatology and Immunology, Beijing Shijitan Hospital, Capital Medical University, took us into ACR 2021 and shared the latest news of the FDA on the safety of rheumatism treatment
.
Safety of Janus Kinase (JAK) Inhibitors JAK inhibitors are oral small-molecule targeted synthetic drugs targeting the JAK-STAT pathway and have proven effective in the treatment of adult patients with moderate to severe active rheumatoid arthritis
.
Tofacitinib, baritinib, and upatinib are the representative drugs of JAK inhibitors.
These three drugs are used to treat rheumatoid arthritis, and tofacitinib is also approved by the FDA for the treatment of psoriasis.
Juvenile idiopathic arthritis such as arthritis and polyarthropathy
.
Severe infections and malignant tumors are listed as black box warnings for these three drugs by the FDA, and thrombosis is listed as black box warnings for baritinib and upatinib
.
Boxed Warnings are warnings issued by the FDA, based on the FDA's assessment of the received post-marketing adverse event reports, and are used to warn doctors and patients of certain drugs that have potential risks, serious side effects, and safety issues
.
The FDA stipulates that this warning must appear in a conspicuous position on the drug packaging in the form of a conspicuous black box
.
Director Wang Yuhua mentioned that since the launch of JAK inhibitors, its efficacy is beyond doubt, but the occurrence of more and more adverse events has also sounded the alarm for us
.
To this end, a tofacitinib post-marketing safety (PMR) study was initiated in 2013 and continued until 2020 to evaluate the long-term safety of tofacitinib in patients with rheumatoid arthritis
.
Figure 1 Tofacitinib post-marketing demand safety (PMR) study This study is a multi-center, randomized, open-label, three-arm trial.
The inclusion criteria are patients older than 50 years old and have at least one cardiovascular risk factor.
The safety of two doses of 10 mg BID tofacitinib and control drugs was evaluated, and the primary endpoints were major adverse cardiovascular events (MACE) (including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and malignant tumors (Excluding non-melanoma skin cancer)
.
The PMR study found that a higher dose (10 mg BID) is a signal to increase mortality and thrombosis
.
It is recommended that patients try to switch from high-dose (10mg) to low-dose therapy (5mg) when the condition permits
.
Only patients with insufficient response or intolerance to tumor necrosis factor (TNF) antagonists should use high-dose tofacitib
.
Figure 2 The results of the PMR study and the safety labels changed by the FDA Based on these safety issues, the FDA recommends reassessing the benefits-risks of these products, and consider limiting the indications
.
In the FDA drug safety promotion in September 2021, warnings and precautions including drug efficacy, MACE, malignant tumors, thrombosis, and mortality have been updated
.
Figure 3 Timeline of updated JAK inhibitors Non-steroidal anti-inflammatory drugs (NSAIDs) need to be cautious during pregnancy NSAIDs are usually used to relieve pain and reduce fever, mainly including aspirin, ibuprofen, naproxen, diclofenac and celecoxib, etc.
Drugs
.
The FDA official website recently updated the relevant warning that using NSAIDs around 20 weeks of pregnancy or later may cause rare but serious kidney problems in the unborn baby
.
This can lead to low levels of amniotic fluid around the baby and possible complications
.
Director Wang Yuhua mentioned that there are also safety issues in the use of NSAIDs in the third trimester, which is about 30 weeks of pregnancy
.
Therefore, before and during pregnancy, the use of NSAID must be extremely cautious
.
In addition, there are reports in the literature that drug reactions with eosinophilia and systemic symptoms (DRESS) occur in patients taking NSAIDs, and those with severe illness may be fatal
.
The typical symptoms of DRESS are fever, skin rash, lymphadenopathy, and/or facial swelling.
Other clinical manifestations may include hepatitis, nephritis, blood abnormalities, myocarditis or myositis, and the manifestations of the disease are variable and may involve other organ systems
.
Director Wang Yuhua shared that if the above symptoms or signs occur, stop immediately and evaluate the patient
.
Figure 4 Patients taking non-steroidal anti-inflammatory drugs appear DRESSFDA's recently approved rheumatism drugs.
With the rapid development of medical technology, many drugs have entered the FDA's field of vision.
Next, follow Director Wang Yuhua to learn about the recently approved rheumatism drugs.
Some updates
.
Figure 5 Some updates on recently approved rheumatism drugs.
Voclosporin was approved by the FDA on November 22, 2021.
It can be used in combination with background immunosuppressive therapy to treat adult patients with active lupus Nephritis, but it is not currently on the market in China
.
Cyclosporine is an analog of cyclosporin A, with an extra single-chain carbon extension, which has a double bond (olefin bond) on the single-carbon chain, which can be combined with cyclophilin A to form a heterodimer The aggregate complex, then binds and inhibits calcineurin, blocks the expression of IL-2 and the immune response mediated by T cells, and stabilizes kidney podocytes
.
Similar to traditional calcineurin inhibitors, nephrotoxicity is an important safety issue for flucyclosporine
.
In addition, adverse events such as hypertension, neurotoxicity, hyperkalemia, QT prolongation, avoiding live vaccines, lymphoma and other malignant tumors, and serious infections need to be paid attention to.
If the patient has pure red blood cell hypoplasia, it needs to be considered to stop
.
Anifrolumab Anifrolumab was approved by the FDA for the treatment of moderate to severe systemic lupus erythematosus (SLE) in adults on July 30, 2021
.
The FDA’s recently updated drug use warnings include adverse events such as serious infections, hypersensitivity reactions (including allergic reactions), and malignant tumors
.
During the use of Anilumab, avoid live vaccines, and it is not recommended to use it with other biological therapies
.
Avacopan Avacopan is a selective complement C5a receptor inhibitor that can inhibit C5a-induced immune cell activation.
It was approved by the FDA on October 7, 2021 for anti-neutrophil antibody (ANCA)-related vasculitis patients combined with glucocorticoids Adjunct to standard treatments such as hormones
.
Recently updated drug use warnings include adverse events such as liver toxicity, severe allergic reactions, hepatitis B virus activation, and serious infections
.
Summary As the understanding of the mechanism of rheumatism continues to deepen, related targeted drugs continue to be developed and innovated
.
For drugs that have entered the clinic, their efficacy is beyond doubt; but for doctors, in addition to efficacy, safety is also an issue that needs to be paid attention to, so that patients can continue to use the drug and better improve the prognosis
.
Expert profile Wang Yuhua, director of the Department of Rheumatology and Immunology, Beijing Shijitan Hospital, Capital Medical University, chief physician, clinical doctor
.
Member of the Youth Committee of the Rheumatology Branch of the Chinese Medical Association, member of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association, member of the Rheumatology Branch of the Beijing Medical Association, and member of the Rheumatology Branch of the Beijing Medical Education Association
.
Project review expert of the Beijing Natural Science Foundation of China, and a young and middle-aged editorial board member of the Chinese Journal of Clinical Immunity and Allergy
.
In recent years, the main research on connective tissue disease with lymphatic involvement has been carried out
.
Digging deep into safety issues is the foundation of medication safety
.
As the understanding of the mechanism of rheumatism continues to deepen, relevant targeted drugs continue to be developed and innovated
.
In the process of innovation and application of drugs such as biological agents and small molecules, the safety and effectiveness of drugs also urgently need to be determined
.
At the just-concluded 2021 American College of Rheumatology (ACR) Annual Meeting (ACR 2021), Dr.
Anil Rajpal, head of the Rheumatology and Transplant Medicine Group of the U.
S.
Food and Drug Administration (FDA) The topic of "the latest news of the issue" was shared
.
In this issue, Wang Yuhua, director of the Department of Rheumatology and Immunology, Beijing Shijitan Hospital, Capital Medical University, took us into ACR 2021 and shared the latest news of the FDA on the safety of rheumatism treatment
.
Safety of Janus Kinase (JAK) Inhibitors JAK inhibitors are oral small-molecule targeted synthetic drugs targeting the JAK-STAT pathway and have proven effective in the treatment of adult patients with moderate to severe active rheumatoid arthritis
.
Tofacitinib, baritinib, and upatinib are the representative drugs of JAK inhibitors.
These three drugs are used to treat rheumatoid arthritis, and tofacitinib is also approved by the FDA for the treatment of psoriasis.
Juvenile idiopathic arthritis such as arthritis and polyarthropathy
.
Severe infections and malignant tumors are listed as black box warnings for these three drugs by the FDA, and thrombosis is listed as black box warnings for baritinib and upatinib
.
Boxed Warnings are warnings issued by the FDA, based on the FDA's assessment of the received post-marketing adverse event reports, and are used to warn doctors and patients of certain drugs that have potential risks, serious side effects, and safety issues
.
The FDA stipulates that this warning must appear in a conspicuous position on the drug packaging in the form of a conspicuous black box
.
Director Wang Yuhua mentioned that since the launch of JAK inhibitors, its efficacy is beyond doubt, but the occurrence of more and more adverse events has also sounded the alarm for us
.
To this end, a tofacitinib post-marketing safety (PMR) study was initiated in 2013 and continued until 2020 to evaluate the long-term safety of tofacitinib in patients with rheumatoid arthritis
.
Figure 1 Tofacitinib post-marketing demand safety (PMR) study This study is a multi-center, randomized, open-label, three-arm trial.
The inclusion criteria are patients older than 50 years old and have at least one cardiovascular risk factor.
The safety of two doses of 10 mg BID tofacitinib and control drugs was evaluated, and the primary endpoints were major adverse cardiovascular events (MACE) (including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and malignant tumors (Excluding non-melanoma skin cancer)
.
The PMR study found that a higher dose (10 mg BID) is a signal to increase mortality and thrombosis
.
It is recommended that patients try to switch from high-dose (10mg) to low-dose therapy (5mg) when the condition permits
.
Only patients with insufficient response or intolerance to tumor necrosis factor (TNF) antagonists should use high-dose tofacitib
.
Figure 2 The results of the PMR study and the safety labels changed by the FDA Based on these safety issues, the FDA recommends reassessing the benefits-risks of these products, and consider limiting the indications
.
In the FDA drug safety promotion in September 2021, warnings and precautions including drug efficacy, MACE, malignant tumors, thrombosis, and mortality have been updated
.
Figure 3 Timeline of updated JAK inhibitors Non-steroidal anti-inflammatory drugs (NSAIDs) need to be cautious during pregnancy NSAIDs are usually used to relieve pain and reduce fever, mainly including aspirin, ibuprofen, naproxen, diclofenac and celecoxib, etc.
Drugs
.
The FDA official website recently updated the relevant warning that using NSAIDs around 20 weeks of pregnancy or later may cause rare but serious kidney problems in the unborn baby
.
This can lead to low levels of amniotic fluid around the baby and possible complications
.
Director Wang Yuhua mentioned that there are also safety issues in the use of NSAIDs in the third trimester, which is about 30 weeks of pregnancy
.
Therefore, before and during pregnancy, the use of NSAID must be extremely cautious
.
In addition, there are reports in the literature that drug reactions with eosinophilia and systemic symptoms (DRESS) occur in patients taking NSAIDs, and those with severe illness may be fatal
.
The typical symptoms of DRESS are fever, skin rash, lymphadenopathy, and/or facial swelling.
Other clinical manifestations may include hepatitis, nephritis, blood abnormalities, myocarditis or myositis, and the manifestations of the disease are variable and may involve other organ systems
.
Director Wang Yuhua shared that if the above symptoms or signs occur, stop immediately and evaluate the patient
.
Figure 4 Patients taking non-steroidal anti-inflammatory drugs appear DRESSFDA's recently approved rheumatism drugs.
With the rapid development of medical technology, many drugs have entered the FDA's field of vision.
Next, follow Director Wang Yuhua to learn about the recently approved rheumatism drugs.
Some updates
.
Figure 5 Some updates on recently approved rheumatism drugs.
Voclosporin was approved by the FDA on November 22, 2021.
It can be used in combination with background immunosuppressive therapy to treat adult patients with active lupus Nephritis, but it is not currently on the market in China
.
Cyclosporine is an analog of cyclosporin A, with an extra single-chain carbon extension, which has a double bond (olefin bond) on the single-carbon chain, which can be combined with cyclophilin A to form a heterodimer The aggregate complex, then binds and inhibits calcineurin, blocks the expression of IL-2 and the immune response mediated by T cells, and stabilizes kidney podocytes
.
Similar to traditional calcineurin inhibitors, nephrotoxicity is an important safety issue for flucyclosporine
.
In addition, adverse events such as hypertension, neurotoxicity, hyperkalemia, QT prolongation, avoiding live vaccines, lymphoma and other malignant tumors, and serious infections need to be paid attention to.
If the patient has pure red blood cell hypoplasia, it needs to be considered to stop
.
Anifrolumab Anifrolumab was approved by the FDA for the treatment of moderate to severe systemic lupus erythematosus (SLE) in adults on July 30, 2021
.
The FDA’s recently updated drug use warnings include adverse events such as serious infections, hypersensitivity reactions (including allergic reactions), and malignant tumors
.
During the use of Anilumab, avoid live vaccines, and it is not recommended to use it with other biological therapies
.
Avacopan Avacopan is a selective complement C5a receptor inhibitor that can inhibit C5a-induced immune cell activation.
It was approved by the FDA on October 7, 2021 for anti-neutrophil antibody (ANCA)-related vasculitis patients combined with glucocorticoids Adjunct to standard treatments such as hormones
.
Recently updated drug use warnings include adverse events such as liver toxicity, severe allergic reactions, hepatitis B virus activation, and serious infections
.
Summary As the understanding of the mechanism of rheumatism continues to deepen, related targeted drugs continue to be developed and innovated
.
For drugs that have entered the clinic, their efficacy is beyond doubt; but for doctors, in addition to efficacy, safety is also an issue that needs to be paid attention to, so that patients can continue to use the drug and better improve the prognosis
.
Expert profile Wang Yuhua, director of the Department of Rheumatology and Immunology, Beijing Shijitan Hospital, Capital Medical University, chief physician, clinical doctor
.
Member of the Youth Committee of the Rheumatology Branch of the Chinese Medical Association, member of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association, member of the Rheumatology Branch of the Beijing Medical Association, and member of the Rheumatology Branch of the Beijing Medical Education Association
.
Project review expert of the Beijing Natural Science Foundation of China, and a young and middle-aged editorial board member of the Chinese Journal of Clinical Immunity and Allergy
.
In recent years, the main research on connective tissue disease with lymphatic involvement has been carried out
.
