This week WebMD, a medical and health news source, and several other internet news sources have reported that the US Food and Drug Administration has updated its warning for a group of drugs called TNF blockers, which it says may cause lymphoma and other cancers in children and adolescents.
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The drugs include infliximab and etanercept, which are used for the treatment of juvenile rheumatoid arthritis (JRA), Crohn’s disease and other inflammatory diseases. Licensing of the drugs in the US may differ from that in the UK.
What is the basis for these current reports?
The Food and Drug Administration (FDA) in the US is responsible for the regulation of foods, dietary supplements, drugs, vaccines and medical devices, and for ongoing safety monitoring. In June last year the organisation announced that it was investigating the possible association between drugs to block tumour necrosis factor alpha (TNF-alpha), a protein involved in mediating the immune and inflammatory response, and the development of lymphoma (cancer of the lymph system) and other cancers in children and young people.
Over a 10-year period the FDA received some 30 reports of these types of cancer in young people taking TNF blockers alongside other immune-suppressive medicines to treat JRA, Crohn’s disease or other conditions. They called for manufacturers to submit information on cancers in children taking these drugs.
When the FDA began its investigation of these reports it stated that the potential benefits of the use of TNF blockers outweigh the potential risks in certain children and young adults. It called for manufacturers to submit reports on any cancer cases, which they included in their investigations.
On August 4 2009 the FDA released a follow-up report requesting a change to the labelling of TNF blockers. They concluded that, based on analysis of 48 childhood cancer cases, “there is an increased risk of lymphoma and other cancers associated with the use of these drugs in children and adolescents”. There is also an increased risk of new psoriasis.
Manufacturers must now add this information to drug literature in the form of a warning on the leaflet inserted into the medicines’ packaging. Patients and professionals are encouraged to report any adverse effects of TNF blockers to the FDA through the MedWatch reporting system they have implemented.
Which cases were the FDA investigating?
The FDA reviewed case reports of 48 childhood cancers in young people also taking TNF blockers. Half of these were lymphomas, including both Hodgkin’s and non-Hodgkin’s lymphoma. Other cancers included leukaemia and melanoma. Some rare cancers, including renal cell carcinoma, liver cancers and leiomyosarcoma (a soft tissue cancer starting in the smooth muscle tissue), were also reported. Unfortunately, 11 of these 48 children died.
In their analysis the FDA concludes that, overall, cases of lymphoma and malignancies in children and young people taking infliximab were higher than would be expected. Children taking etanercept had higher than expected rates of lymphomas, but overall rates of cancer were as expected. The TNF blockers adalimumab and certolizumab were not included in their analysis because these drugs are not often used in children.
The FDA says that, in the cases of childhood cancer that they investigated, the majority of the patients (88%) were also taking other immunosuppressive medicines such as azathioprine or methotrexate, which carry warnings about increased cancer risk. It is, therefore, difficult to determine the possible causes of these cancers, but the role of TNF blockers cannot be excluded.
What are TNF blockers?
TNF blockers work by suppressing the immune system through blocking TNF, a substance that causes inflammation, which can lead to bone and tissue damage. This action makes them useful for treating immune-related disease. The prescribing guidelines for the four TNF blockers that are currently available in the USA (Remicade, Enbrel, Humira and Cimzia) already contains a warning about the possible risk of cancer.
The FDA reports that manufacturers of these drugs are required to report any cases of cancer in children using these medications, so that the FDA can monitor the situation. In addition, the manufacturer of Cimzia will conduct a 10-year study starting in 2009 that will assess the impact of the drug, with particular reference to new cancers.
Are TNF blockers used in the UK?
In the UK, the licensed TNF-alpha blockers are:
- adalimumab (Humira),
- etanercept (Enbrel), and
- infliximab (Remicade).
The only drug that may be prescribed for children is etanercept, which is licensed for use in juvenile arthritis only. NICE guidance (2002) advises that this drug be used only in children aged four to 17 who have had an inadequate response to, or been intolerant of, methotrexate (a disease-modifying antirheumatic drug).
Etanercept is licensed for prescription, in accordance with the British Paediatric Rheumatology Group, by a consultant who regularly sees the child and who registers the child with the Biologics Registry, where all details of dosage, response and toxicity are regularly reported.
Infliximab and adalimumab are not licensed for use in children with arthritic diseases. Regarding inflammatory bowel disorders, infliximab is licensed for the treatment of only adult cases of Crohn’s disease. Adalimumab may also be used in adults with Crohn’s disease, but its use for this condition is currently undergoing NICE review, as is infliximab. Neither drug is licensed as a treatment for children or adolescents under 18 years.
What specific changes has the FDA called for?
The FDA has specifically requested that manufacturers:
- Update their boxed warning on prescribing information to ensure healthcare professionals are alerted to the association between use of TNF blockers and increased risk of lymphoma and other malignancies.
- Update the adverse events section of the drug information sheets to include information on possible new-onset psoriasis.
- Revise the medication guide section to reflect this new information.
What is the advice for patients?
The FDA has said that patients should:
- Be aware that taking TNF blockers may increase the risk of developing lymphoma, leukaemia and other cancers.
- Be aware that taking TNF blockers may increase the risk of developing psoriasis or worsen pre-existing psoriasis.
- 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.
- Review the printed medication guide that comes packaged with TNF blockers.
- Not stop or change their use of medicines that have been prescribed without first talking to a suitable healthcare professional.
- Pay close attention for any signs or symptoms of cancer, such as unexplained weight loss or fatigue, easy bruising or bleeding, or swollen lymph nodes in the neck, underarms or groin. Any possible signs or symptoms should be promptly discussed with a healthcare professional.
In the face of overwhelming evidence that the drugs cause cancer, the FDA would withdraw them from use. However, this is not the current view of the FDA. The FDA is now working with manufacturers to find ways to understand and quantify the association between cancer and treatment with TNF blockers. Based on these new recommendations, patients should not change their own medication without speaking to their doctor.
Links to the headlines
Child, Teen Cancers Linked to TNF Blockers. Web MD, August 6 2009
FDA: Cancer Warnings Required for TNF Blockers. August 4 2009