Singapore Government
Health Science Authority
Singapore Government
Home

2 Jul 2008: Tumor necrosis factor-alpha antagonists and serious skin reactions

Tumor necrosis factor-alpha (TNF-alpha), is a cytokine produced by monocytes and macrophages and has a role in promoting an inflammatory response which may lead to the development of certain autoimmune disorders such as rheumatoid arthritis or Crohn's disease. TNF-alpha antagonists are biological protein molecules designed to block the TNF-alpha's inflammatory responses. Since 2002, HSA has registered three TNF-alpha antagonists:
  • Adalimumab (Humira® 40mg/0.8mL, Abbott)
  • Etanercept (Enbrel® 25mg, Wyeth)
  • Infliximab (Remicade® 100mg, Centocor BV)

 
TNF-alpha antagonists are currently locally approved for the management of severe arthritic conditions and Crohn's' disease (infliximab only). As TNF-alpha antagonists are protein molecules, they have the capability to ellicit an immune response possibly leading to hypersensitivity reactions.


Serious dermatological adverse reactions

Since August 1998, following the first marketing authorization of infliximab, the US Food and Drug Administration (FDA) has been receiving adverse drug reports (ADR) of serious cutaneous adverse reactions associated with the use of adalimumab, etanercept and infliximab. The adverse reactions, from both domestic and overseas reports include erythema multiforme (EM), Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (refer to Table 1 for details). To date, there are:
  • 7 reports associated with adalimumab
  • 22 reports associated with etanercept
  • 21 reports associated with infliximab

 
The evaluation of the potential of TNF-alpha antagonists' capability to elicit serious dermatological reactions are difficult as other confounding factors were present. A significant number of these patients were co-administered with one or more medications such as carbamazepine, amoxicillin, ciprofloxacin, methotrexate and celecoxib, which are also known to be associated with EM, SJS and TEN. However, a certain number of these cases yielded positive rechallenge and dechallenge outcomes, supporting the association of serious skin reactions with the use of adalimumab, etanercept and infliximab. Despite the lack of information, FDA reported that there was a time related relationship between the first dose or the most recent dose of TNF-alpha antagonists and the time to onset of the skin reaction.
 
Table 1: Summary of demographics and characteristics of the serious dermatological cases reported by US FDA 
 

 

Infliximab

Etanercept

Adalimumab

Male

5

7

1

Female

16

14

6

Unknown

-

1

-

Age

 

 

 

Median

54

53

51

Range

27–70 (data provided for 20 patients)

16–84

23–61

Skin reactions

 

 

 

Erythema multiforme (EM)

15

13

4

Stevens Johnson syndrome (SJS)

5

4

2

Toxic epidermal necrolysis (TEN)

1

4

-

SJS/TEN

-

1

-

EM/SJS

-

-

1

Time to onset since first dose (days)

 

 

 

Median

28

50

60

Range

4 days – 18 months (Data provided for 11 patients)

5 days – 52 months

6 days –  3 years

Other medications

15 (71%) were on concomitant medications e.g. carbamazepine, diltiazem, frusemide / hydrochlorothiazide, leflunomide, methotrexate, mercaptopurine, meloxicam, naproxen, rofecoxib, sulfasalazine, sertraline

15 (68%) were on concomitant medications e.g. aspirin, amoxicillin, celecoxib, ciprofloxacin, diclofenac, etoricoxib, ethinyl estradiol / levonorgestrol, flurbiprofen, hydroxychloroquine, methotrexate, indapamide, isoniazid, lamotrigine, meloxicam, naproxen, rofecoxib, sulfasalazine, terbinafine, venlafaxine, warfarin

2 (29%) on methotrexate

 


Actions taken in the US

The US product label for infliximab has been updated to include these post-marketing findings of serious skin adverse drug reactions. The FDA is currently reviewing whether there is a need to revise the product labels for etanercept and adalimumab and will continue to monitor the situation through their MedWatch program. Healthcare professionals and patients have been advised to maintain vigilance for such skin reactions associated with the use of adalimumab, etanercept and infliximab.


Local findings and regulatory actions

In Singapore, the local package insert of infliximab has been updated to reflect these recent post-marketing findings of serious skin reactions. HSA is currently reviewing the package inserts of the other two TNF-alpha antagonists. .
 
HSA has not received any local reports of serious skin-related adverse drug reactions associated with the use of TNF-alpha antagonists. Healthcare professionals are encouraged to report any suspected adverse drug reactions associated with TNF-alpha antagonists to HSA.


Reference

1. FDA Drug Safety Newsletter. Winter 2008.


Last updated on 02 Jul 2010 16:58:32
Best viewed using Internet Explorer 7.0 and above. | Privacy Statement | Terms of Use | HSA Data Protection Policy | Rate Our Website
Health Sciences Authority © 2007-2011. All Rights Reserved.