Early Communication about the Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers

AMPLIACION DE INFORMACIÓN DADA AYER
Follow-up to the June 4, 2008 Early Communication about the Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)
August 4, 2009

FDA has completed its analysis of tumor necrosis factor (TNF) blockers and has concluded that there is an increased risk of lymphoma and other cancers associated with the use of these drugs in children and adolescents. This new safety information is now being added to the Boxed Warning for these products.

In addition, FDA has identified new safety information related to the occurrence of leukemia and new-onset psoriasis in patients treated with TNF blockers. The current prescribing information for TNF blockers does contain a warning for malignancies, but does not specifically mention leukemia. Therefore, FDA is requiring this information to be incorporated into the prescribing information for TNF blockers. FDA is also requiring updates to the current Medication Guide to help patients understand the risks associated with TNF blocker therapy.

TNF blockers are approved for the treatment of one or more of a number of immune system diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis.

These labeling changes are being required under the authorities granted to FDA by the Food and Drug Administration Amendments Act (FDAAA) of 2007.

The FDA urges both healthcare professionals and patients to report side effects from the use of TNF blockers to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information at the bottom of this page.


FDA NOTE TO CORRESPONDENTS
For Immediate Release: Aug. 4, 2009

Media Inquiries: Office of Public Affairs, 301-796-4540
Consumer Inquiries: 888-INFO-FDA

FDA: Cancer Warnings Required for TNF Blockers
The U.S. Food and Drug Administration is requiring stronger warnings in the prescribing information for a class of drugs known as TNF blockers. The warnings, which include an updated boxed warning, highlight the increased risk of cancer in children and adolescents who receive these drugs to treat juvenile rheumatoid arthritis, the inflammatory bowel disorder, Crohn’s disease, and other inflammatory diseases.

In addition, the FDA is working with manufacturers to explore new ways to further define the risk of cancer in children and adolescents who use these drugs.

TNF blockers target and neutralize tumor necrosis factor-alpha (TNF-α), a protein that, when overproduced in the body due to chronic inflammatory diseases, can cause inflammation and damage to bones, cartilage and tissue. The drugs in this class include Remicade (infliximab), Enbrel (etancercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab).

Today’s action is based on the completion of an investigation first announced by the FDA in June 2008. An analysis of U.S. reports of cancer in children and adolescents treated with TNF-blockers showed an increased risk of cancer, occurring after 30 months of treatment on average. About half of the cancers were lymphomas, a type of cancer involving cells of the immune system. Some of the reported cancers were fatal.

Additional required updates to the prescribing information include incorporation of reports of psoriasis associated with the use of TNF blockers.

For more information see:

Update to June 2008 Early Communication about an Ongoing Safety Review of TNF Blockers

Information for Healthcare Professionals

June 2008 Early Communication about an Ongoing Safety Review of TNF Blockers


Information for Healthcare Professionals: Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)
FDA ALERT [8/4/2009]:
FDA is requiring the manufacturers of TNF 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 TNF blockers.

In addition to the updated Boxed Warning, FDA is requiring several other changes to the prescribing information for TNF blockers to warn of and mitigate the risks associated with these drugs. These changes are based on additional safety reviews and include a(n):

Update to the Warnings section describing reported cases of leukemia in adults, adolescents, and children. Changes to the Warnings section of the labeling will also include additional information on malignancies in children and adolescents (see also Boxed Warning information above).
Update to the Adverse Events section to include information on reported cases of new-onset psoriasis.
Revised Medication Guide to reflect this new safety information.
This new safety information is based on FDA’s completed analysis of TNF blockers and reports of lymphoma and other cancers in children and adolescents, a second analysis of TNF 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.

TNF blockers are approved for the treatment of one or more of a number of immune system diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis.

FDA is requiring these updates to the prescribing information of TNF blockers under the authorities granted to FDA by the Food and Drug Administration Amendments Act (FDAAA) of 2007.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.


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To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program using the information at the bottom of this page.

Considerations for Healthcare Professionals:

Discuss with patients and families the increased risk of developing cancer in children and adolescents, taking into account the clinical utility of TNF blockers, the risks/benefits of other immunosuppressive therapies, and the risks associated with untreated illness.
Be aware of the possibility and monitor for the emergence of malignancies during and after treatment with TNF blockers.
Be aware of the possibility and monitor for the emergence or worsening of psoriasis during treatment with TNF blockers, particularly pustular and palmoplantar forms of psoriasis.
Understand that some immune-related diseases, such as Crohn’s, have been shown to increase cancer risk independent of treatment with TNF blockers while for others, such as juvenile idiopathic arthritis (JIA), it is unknown whether there is an increased cancer risk.
Inform patients, their families, and caregivers of the signs and symptoms of malignancies or psoriasis so they are aware of and able to notify their healthcare professional of any unusual signs or symptoms.
Information for Patients

Be aware that taking TNF blockers may increase the risk of developing lymphoma, leukemia, and other cancers.
Be aware that taking TNF blockers may increase the risk of developing psoriasis and may worsen pre-existing psoriasis.
Review the Medication Guide that accompanies TNF blockers.
Do not stop or change medicines that have been prescribed without first talking with a knowledgeable healthcare professional.
Pay close attention for any signs or symptoms of cancer such as unexplained weight loss or fatigue, swollen lymph nodes in the neck, underarms or groin, or easy bruising or bleeding. Promptly discuss any signs and symptoms with a healthcare professional.
Pay close attention for any signs or symptoms of new onset psoriasis or worsening psoriasis such as red scaly patches or raised bumps on the skin that are filled with pus.
Data Summary: Pediatric Malignancies
On June 4th 2008, FDA issued an Early Communication about an ongoing safety review of TNF 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 TNF blockers. At that time, FDA requested that manufacturers of TNF 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 TNF 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 TNF blockers. However, due to the relatively rare occurrence of these cancers, the limited number of pediatric patients treated with TNF blockers, and the possible role of other immunosuppressive therapies used concomitantly with TNF blockers, FDA is unable at this time to fully characterize the strength of the association between using TNF 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 TNF blocker manufacturers. In addition, FDA is working with TNF blocker manufacturers to explore new ways to further define the risk of malignancy in children and adolescents using TNF blockers.

Data Summary: Leukemia
FDA reviewed 147 post-marketing reports of leukemia in all patients, including adults, using TNF 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 TNF 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 TNF blockers. However, based on the available data, FDA concludes there is a possible association between treatment with TNF blockers and the development of leukemia in all patients treated with these drugs. The current prescribing information for TNF blockers contains a warning for malignancies, but does not specifically mention leukemia. Therefore, to alert healthcare professionals to this possible association, FDA is requiring the incorporation of information on post-marketing reports of leukemia into the prescribing information for TNF blockers.

Data Summary: 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 TNF 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 TNF 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 TNF blocker. None of the cases reported pre-existing psoriasis prior to the initiation of TNF blocker therapy.

Due to the number of reported cases and the temporal relationship between the initiation of TNF 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 TNF blockers.