Tumor Necrosis Factor (TNF) Blockers 2013
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Data Summary
Pediatric Malignancies
On June 4th 2008, FDA issued an Early Communication about an ongoing safety review of tumor necrosis factor
blockers and the development of lymphoma and other cancers in children and adolescents. The Early
Communication was based on approximately 30 reports of cancer in children and adolescents treated with tumor
necrosis necrosis blockers. At that time, FDA requested that manufacturers of tumor necrosis factor blockers
approved for use in children (Enbrel, Humira, and Remicade) submit information about all cases of cancer reported
in children using these products. Cimzia, approved in April 2008, and Simponi, approved in April 2009, were not
included in FDA’s review because they are not approved for use in children and were minimally used during the
review period.
The completed FDA analysis identified 48 cases of malignancies in children and adolescents. Of the 48 cases
reviewed by FDA, approximately half were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. Other
malignancies reported include leukemia, melanoma, and solid organ cancers. Malignancies such as
leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which are rare in children, were also reported. Of
the 48 cases of malignancy, there were 11 deaths. The causes of death included hepatosplenic T-cell lymphoma (9
cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission
of the lymphoma.
The FDA analysis showed that U.S. reporting rates for cases of malignancy with Remicade (infliximab) were
consistently higher compared to expected background rates for lymphomas and all malignancies. The malignancy
reporting rates for Enbrel (etancercept) were also higher than background rates for lymphomas, but were similar to
background rates for all malignancies. The malignancy reporting rates for Humira (adalimumab) and Cimzia
(certolizumab pegol) were not calculated during the analysis because of minimal use in pediatric patients. Simponi
(golimumab) was not approved at the time of the analysis and therefore was not included. The observed reporting
rates offer very limited inference into the potential differences in malignancy risk among the TNF blockers because
of uncertainties about actual patient exposure to treatment and the possibility of underreporting of malignancy cases.
The majority of the 48 patients (88%) were also using other immunosuppressive medications such as azathioprine
and methotrexate, which currently have warnings of increased risk of lymphoma in their prescribing information.
Although there were other contributory factors, the role of tumor necrosis factor blockers in the development of
malignancies in children and adolescents could not be excluded.
Therefore, FDA concludes there is an increased risk of malignancy with tumor necrosis factor blockers. However,
due to the relatively rare occurrence of these cancers, the limited number of pediatric patients treated with tumor
necrosis factor blockers, and the possible role of other immunosuppressive therapies used concomitantly with tumor
necrosis factor blockers, FDA is unable at this time to fully characterize the strength of the association between
using tumor necrosis factor blockers and developing a malignancy. Additional data are expected from the ongoing
long term, observational, post-marketing studies and registries that are being conducted by the tumor necrosis
factor blocker manufacturers. In addition, FDA is working with tumor necrosis factor blocker manufacturers to
explore new ways to further define the risk of malignancy in children and adolescents using tumor necrosis factor
blockers.
Leukemia
FDA reviewed 147 post-marketing reports of leukemia in all patients, including adults, using tumor necrosis factor
blockers. Of the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and
chronic myeloid leukemia (23 cases) were the most frequently classified types of leukemia reported. Four pediatric
cases of leukemia were reported in the review. Most patients (61%) were also receiving other immunosuppressive
therapies. There were a total of 30 deaths reported. In 26 of the 30 deaths, the cause was reported to be leukemia,
and the event was associated with the use of tumor necrosis factor blockers. The average time to onset of leukemia
was within the first 1 to 2 years of therapy.
The interpretation of these findings is complicated by the fact that published epidemiological studies suggest that
patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment with tumor
necrosis factor blockers. However, based on the available data, FDA concludes there is a possible association
between treatment with tumor necrosis factor blockers and the development of leukemia in all patients treated with
these drugs.
Psoriasis
In a separate analysis, FDA reviewed 69 cases of new onset psoriasis, including pustular (17 cases) and
palmoplantar (15 cases), in all patients using tumor necrosis factor blockers for treatment of autoimmune and
rheumatic conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, there were 2 pediatric reports of
new onset psoriasis. The development of psoriasis during treatment with tumor necrosis factor blockers occurred
with varying duration from weeks to years after drug initiation. Twelve of the psoriasis cases resulted in
hospitalization, which was the most severe outcome reported. The majority of patients experienced improvements of
their psoriasis following discontinuation of the tumor necrosis factor blocker. None of the cases reported pre-
existing psoriasis prior to the initiation of tumor necrosis factor blocker therapy.
Due to the number of reported cases and the temporal relationship between the initiation of tumor necrosis factor
blockers and development of psoriasis, FDA concludes there is a possible association between the development of
psoriasis and use of these drugs. Therefore, FDA is requiring an update to the Adverse Events section of the
prescribing information to inform healthcare professionals about reported cases of new-onset psoriasis associated
with the use of tumor necrosis factor blockers.
Hepatosplenic T-Cell Lymphoma
FDA has also informed the public that it continues to receive reports of a rare cancer of white blood cells (known as
Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s
disease and ulcerative colitis with tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or
mercaptopurine. [3]
Reference
[1] Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as
Remicade, Enbrel, Humira, and Cimzia) 6/4/2008
[2] FDA Alert, August 4, 2009
[3] FDA Alert, 04-14-2011
Pediatric Malignancies
On June 4th 2008, FDA issued an Early Communication about an ongoing safety review of tumor necrosis factor
blockers and the development of lymphoma and other cancers in children and adolescents. The Early
Communication was based on approximately 30 reports of cancer in children and adolescents treated with tumor
necrosis necrosis blockers. At that time, FDA requested that manufacturers of tumor necrosis factor blockers
approved for use in children (Enbrel, Humira, and Remicade) submit information about all cases of cancer reported
in children using these products. Cimzia, approved in April 2008, and Simponi, approved in April 2009, were not
included in FDA’s review because they are not approved for use in children and were minimally used during the
review period.
The completed FDA analysis identified 48 cases of malignancies in children and adolescents. Of the 48 cases
reviewed by FDA, approximately half were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. Other
malignancies reported include leukemia, melanoma, and solid organ cancers. Malignancies such as
leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which are rare in children, were also reported. Of
the 48 cases of malignancy, there were 11 deaths. The causes of death included hepatosplenic T-cell lymphoma (9
cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission
of the lymphoma.
The FDA analysis showed that U.S. reporting rates for cases of malignancy with Remicade (infliximab) were
consistently higher compared to expected background rates for lymphomas and all malignancies. The malignancy
reporting rates for Enbrel (etancercept) were also higher than background rates for lymphomas, but were similar to
background rates for all malignancies. The malignancy reporting rates for Humira (adalimumab) and Cimzia
(certolizumab pegol) were not calculated during the analysis because of minimal use in pediatric patients. Simponi
(golimumab) was not approved at the time of the analysis and therefore was not included. The observed reporting
rates offer very limited inference into the potential differences in malignancy risk among the TNF blockers because
of uncertainties about actual patient exposure to treatment and the possibility of underreporting of malignancy cases.
The majority of the 48 patients (88%) were also using other immunosuppressive medications such as azathioprine
and methotrexate, which currently have warnings of increased risk of lymphoma in their prescribing information.
Although there were other contributory factors, the role of tumor necrosis factor blockers in the development of
malignancies in children and adolescents could not be excluded.
Therefore, FDA concludes there is an increased risk of malignancy with tumor necrosis factor blockers. However,
due to the relatively rare occurrence of these cancers, the limited number of pediatric patients treated with tumor
necrosis factor blockers, and the possible role of other immunosuppressive therapies used concomitantly with tumor
necrosis factor blockers, FDA is unable at this time to fully characterize the strength of the association between
using tumor necrosis factor blockers and developing a malignancy. Additional data are expected from the ongoing
long term, observational, post-marketing studies and registries that are being conducted by the tumor necrosis
factor blocker manufacturers. In addition, FDA is working with tumor necrosis factor blocker manufacturers to
explore new ways to further define the risk of malignancy in children and adolescents using tumor necrosis factor
blockers.
Leukemia
FDA reviewed 147 post-marketing reports of leukemia in all patients, including adults, using tumor necrosis factor
blockers. Of the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and
chronic myeloid leukemia (23 cases) were the most frequently classified types of leukemia reported. Four pediatric
cases of leukemia were reported in the review. Most patients (61%) were also receiving other immunosuppressive
therapies. There were a total of 30 deaths reported. In 26 of the 30 deaths, the cause was reported to be leukemia,
and the event was associated with the use of tumor necrosis factor blockers. The average time to onset of leukemia
was within the first 1 to 2 years of therapy.
The interpretation of these findings is complicated by the fact that published epidemiological studies suggest that
patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment with tumor
necrosis factor blockers. However, based on the available data, FDA concludes there is a possible association
between treatment with tumor necrosis factor blockers and the development of leukemia in all patients treated with
these drugs.
Psoriasis
In a separate analysis, FDA reviewed 69 cases of new onset psoriasis, including pustular (17 cases) and
palmoplantar (15 cases), in all patients using tumor necrosis factor blockers for treatment of autoimmune and
rheumatic conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, there were 2 pediatric reports of
new onset psoriasis. The development of psoriasis during treatment with tumor necrosis factor blockers occurred
with varying duration from weeks to years after drug initiation. Twelve of the psoriasis cases resulted in
hospitalization, which was the most severe outcome reported. The majority of patients experienced improvements of
their psoriasis following discontinuation of the tumor necrosis factor blocker. None of the cases reported pre-
existing psoriasis prior to the initiation of tumor necrosis factor blocker therapy.
Due to the number of reported cases and the temporal relationship between the initiation of tumor necrosis factor
blockers and development of psoriasis, FDA concludes there is a possible association between the development of
psoriasis and use of these drugs. Therefore, FDA is requiring an update to the Adverse Events section of the
prescribing information to inform healthcare professionals about reported cases of new-onset psoriasis associated
with the use of tumor necrosis factor blockers.
Hepatosplenic T-Cell Lymphoma
FDA has also informed the public that it continues to receive reports of a rare cancer of white blood cells (known as
Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s
disease and ulcerative colitis with tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or
mercaptopurine. [3]
Reference
[1] Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as
Remicade, Enbrel, Humira, and Cimzia) 6/4/2008
[2] FDA Alert, August 4, 2009
[3] FDA Alert, 04-14-2011
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Tumor Necrosis Factor (TNF)
Tumor necrosis factor (TNF) is a cytokine released by macrophages in the presence of an endotoxin and may be
able to attack and destroy cancerous tumors. However, tumor necrosis factor can also exacerbate certain chronic
inflammatory diseases. Cytokines are protein molecules secreted by cells of the immune system that serve to
regulate the immune system.
able to attack and destroy cancerous tumors. However, tumor necrosis factor can also exacerbate certain chronic
inflammatory diseases. Cytokines are protein molecules secreted by cells of the immune system that serve to
regulate the immune system.
Tumor Necrosis Factor (TNF) Blockers
Tumor necrosis factor blockers are approved for the treatment of one or more of a number of immune system
diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s
disease, and ankylosing spondylitis. Tumor necrosis factor blockers suppress the immune system by blocking the
activity of Tumor Necrosis Factor.
As discussed in last section, tumor necrosis factor is a substance in the body that can cause inflammation and lead
to immune system-related diseases. There are about four tumor necrosis factor blockers available in the United
States. Remicade, Enbrel, Humira, Cimzia and Simponi are each approved to treat one or more of a number of
immune system diseases including Juvenile Idiopathic Arthritis, rheumatoid arthritis, psoriatic arthritis, plaque
psoriasis, Crohn’s disease, and ankylosing spondylitis. Remicade is approved for use in children to treat Crohn’s
disease. Enbrel and Humira are approved for use in children to treat Juvenile Idiopathic Arthritis. [1]
On August 4, 2009, FDA required the manufacturers of tumor necrosis factor blockers to update the Boxed Warning
in the prescribing information to alert healthcare professionals of an increased risk of lymphoma and other
malignancies in children and adolescents treated with tumor necrosis factor blockers. [2] This safety information was
based on FDA’s completed analysis of tumor necrosis factor blockers and reports of lymphoma and other cancers
in children and adolescents, a second analysis of tumor necrosis factor blockers and post-marketing leukemia
reports in all patients, as well as a post-marketing evaluation of new-onset psoriasis in patients treated with these
drugs. [2]
__________________________________________________________________________________________
Tumor necrosis factor blockers are approved for the treatment of one or more of a number of immune system
diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s
disease, and ankylosing spondylitis. Tumor necrosis factor blockers suppress the immune system by blocking the
activity of Tumor Necrosis Factor.
As discussed in last section, tumor necrosis factor is a substance in the body that can cause inflammation and lead
to immune system-related diseases. There are about four tumor necrosis factor blockers available in the United
States. Remicade, Enbrel, Humira, Cimzia and Simponi are each approved to treat one or more of a number of
immune system diseases including Juvenile Idiopathic Arthritis, rheumatoid arthritis, psoriatic arthritis, plaque
psoriasis, Crohn’s disease, and ankylosing spondylitis. Remicade is approved for use in children to treat Crohn’s
disease. Enbrel and Humira are approved for use in children to treat Juvenile Idiopathic Arthritis. [1]
On August 4, 2009, FDA required the manufacturers of tumor necrosis factor blockers to update the Boxed Warning
in the prescribing information to alert healthcare professionals of an increased risk of lymphoma and other
malignancies in children and adolescents treated with tumor necrosis factor blockers. [2] This safety information was
based on FDA’s completed analysis of tumor necrosis factor blockers and reports of lymphoma and other cancers
in children and adolescents, a second analysis of tumor necrosis factor blockers and post-marketing leukemia
reports in all patients, as well as a post-marketing evaluation of new-onset psoriasis in patients treated with these
drugs. [2]
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