The COX-2 inhibitors are not the only arthritis drugs under scrutiny at the moment. The US Food and Drug Administration is also taking a good hard look at the tumour necrosis factor (TNF)-blocking drugs, also used to treat rheumatoid arthritis, following serious problems with these drugs – whether used singly or in combination.
TNF-blockers, which include Amgen and Wyeth’s Enbrel, Abbott’s Humira and Centocor’s Remicade, are a new class of drugs that block the overproduction of TNF, an inflammation-regulating protein which medicine believes is behind the inflammation seen in rheumatoid arthritis and other autoimmune disorders. By limiting the production of this protein, these drugs – which are biologically engineered – supposedly relieve the worst and most painful symptoms of the disease.
Nevertheless, an FDA advisory panel met last year to determine whether the TNF-blockers were behind some 170 cases of lymphoma that occurred among users of these drugs in the last five years. In the last few months, the advisory panel has issued several stiff warnings about these products.
The FDA asked manufacturer Centocor, a subsidiary of Johnson & Johnson, to revise its warnings as given in the prescribing information for best-selling arthritis drug Remicade, also used to treat Crohn’s disease, following evidence that it may cause cancer. In recent studies of all TNF-blocking agents, those taking these drugs for arthritis had three times the incidence of lymphoma as the general public.
Centocor itself admitted that, in all its controlled trials, their drug had a six-times higher incidence of this cancer than expected. Those most at risk included those with Crohn’s disease or RA – the very population prescribed the drug and often also taking immunosuppressant drugs at the same time.
The FDA has advised all manufacturers producing TNF-blocking drugs to add a box warning of the drug’s potential to cause malignancy to their product information sheets.
This is a huge blow for Centocor, as Remicade was the 28th top-selling drug in 2003, with sales of $1.5 billion in the US alone. It is also Remicade’s second advisory in six weeks. The FDA asked for its first warning following cases of potentially fatal blood (leukopenia, neutropenia and pancytopenia) and central nervous system presentations of systemic vasculitis among patients taking the drug. So far, at least 12 people – taking Remicade in combination with other drugs – have died worldwide, although the FDA cannot prove a direct causal link with the drug. Nevertheless, the section in the prescribing literature covering the drug’s adverse drug reactions must now mention these potential side-effects as well as pericardial effusion (fluid in the heart tissue).
In early November, the FDA followed suit with a mandated revision to the warnings section of the prescribing information for Humira (adalimumab). It must now include information concerning new side-effects when the drug is used in combination with anakinra (Kineret), another biological agent for rheumatoid arthritis. The side-effects of Humira now include anaphylactic reactions, and serious blood disorders such as pancytopenia and aplastic anaemia