Three TNF blocking agents are registered in Singapore and are licensed for the treatment of rheumatoid arthritis: infliximab (Remicade®, Centocor), etanercept (Enbrel®, Wyeth) and adalimumab (Humira®, Abbott). These monoclonal antibodies bind to human TNF which is a pro-inflammatory and immunoregulatory cytokine that, when overexpressed, mediates chronic inflammation in diseases such as rheumatoid arthritis. Several uncommon but serious adverse events have come to light through post-marketing surveillance.

HSA would like to highlight some important safety information concerning this class of drugs.

There are more cases of lymphoma amongst patients receiving TNF blocking agents compared with control patients in clinical trials. The standardised incidence ratios of lymphoma are approximately 3-fold, 5-fold and 7-fold higher in patients treated with Enbrel®, Humira® and Remicade®, respectively than expected in the general population. Nine cases of lymphoma were observed in 3,389 patients (~7,400 patient-year) on Enbrel®, 10 cases of lymphoma in 2,468 patients (~4870 patient-year) on Humira® and 6 cases of lymphoma in 2,421 patients (~4,100 patient-year) on Remicade®. (It should be noted that adverse reaction rates observed in clinical trials of a particular drug cannot be compared directly to the rates in other clinical trials of other TNF blocking agents because the trial designs and patient population studies differ among the three TNF blocking agents and between the various studies. No head-to-head trials for these drugs have been studied.) Patients with rheumatoid arthritis, in particular, those with highly active disease may have a higher risk for the development of lymphoma.

Other malignancies beside lymphoma have been observed in patients on TNF blocking therapies. The potential role of TNF blocking agents in the development of malignancies is not known.

Rare cases of pancytopenia including aplastic anaemia, some of which led to fatal outcomes, have been reported in patients receiving TNF blocking agents. Caution should be exercised in patients when using these drugs in patients who have a history of blood dyscrasias. Doctors should advise patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g. persistent fever, sore throat) while on any of these products. Discontinuation of therapy should be considered in patients with confirmed significant haematological abnormalities.

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis have been reported [~3 patients in clinical trials and 35 patients in the voluntary post-marketing reports] in association with Remicade®. However, a causal relationship between Remicade® and these events has not been established. These severe reactions were reported to occur from 2 weeks to more than 1 year after initiation of Remicade®; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Remicade® should be discontinued if a patient presents with jaundice and/or marked liver enzyme elevations (e.g. ≥5 times the upper limit of normal) and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade® without progression to severe hepatic injury.

HSA is working with the affected companies to make the necessary changes to the local package inserts.

Update on the TNF blocking agents. Briefing Document for FDA Arthritis Advisory Committee, 4 March 2003