MEDIA STATEMENT

17th February 2005

Lyell's Syndrome and Stevens-Johnson Syndrome

Erythema multiforme

Erythema multiforme is a type of hypersensitivity reaction that occurs in response to medications, infections, or illness. Medications associated with erythema multiforme include sulfonamides, penicillins, barbiturates, and phenytoin. The exact cause is unknown. The disorder is believed to involve damage to the blood vessels of the skin with subsequent damage to skin tissues. Erythema multiforme may present with a classic skin lesions with or without systemic symptoms. Where the blistering and mucosal lesions are severe, the disease is termed Stevens-Johnson syndrome. This is usually associated with high fever and sometimes also anterior uveitis, pneumonia, renal failure, polyarthritis, or diarrhoea.

Lyell's Syndrome (Toxic epidermal necrolysis)

This is a rare variety of erythema with acute epithelial necrosis affecting all areas of the skin.   This sometimes called 'scalded skin syndrome' because of its clinical appearance. It is usually acute in onset and may be preceded by various patterns of blistering also known as toxic erythema. Pressure and shearing stresses on the skin tend to encourage the extension of the blisters. There are two varieties of the disease: the first is due to a staphylococcus and particularly affects children - the blistering and the resulting erosions are very superficial and they are due to a split at the level of the stratum granulosum; the second is a drug reaction or a toxic consequence of malignant disease or its therapy.   In both cases, the entire epidermis is necrotic. The drugs associated with Lyell's syndrome are sometimes sulphonamides, barbiturates, phenytoin, pyrazolone derivatives, or phenolphthalein. A number of other drugs are more rarely implicated.

In the published literature, very little information is available on the subject of cutaneous adverse effects related to low dose, short-term use of ibuprofen. However, a literature search found 3 case reports of Stevens-Johnson Syndrome in which ibuprofen was implicated (Sternlieb and Robinson 1978; Srivastava et al. 1998, Taghian M 2004).

Rainsford (1999) reports several studies that have investigated the occurrence of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) associated with non-steroidal anti-inflammatory drug (NSAID) use. Chan et al. (1990) performed a retrospective survey of EM, SJS and TEN cases over a 14-year period (representing approximately 3.8 million person years) and concluded that NSAIDs were not implicated in these diseases. Roujeau et al. (1995) reviewed combined data from France, Germany, Italy and Portugal and found that, among NSAIDs, only oxicam derivatives (e.g. piroxicam) were significantly associated with these diseases.   The risks associated with propionic acid NSAIDs and diclofenac were not significantly increased. According to Halpern et al (Rainsford 1999), cutaneous reactions accounted for 25.5% of all suspected undesirable effects of ibuprofen reported to the Committee on the Safety of Medicines in the UK. Of these cutaneous reactions, the frequency of spontaneously reported cases of EM / SJS and TEN was 3% (Halpern, 1994), equating to approximately 0.77% of all suspected undesirable effects reported in the UK. However these data apply to all formats of ibuprofen in both prescription and non-prescription use.

Further examination of the data that has accumulated since 1991, in a time of increased distribution and availability of ibuprofen, suggests the Halpern analysis to have been over estimated.

The MHRA in the UK has an Adverse Drug Reactions On-Line Information Tracking (ADROIT) database, which contains information on all suspected reactions reported to the agency. The physicians, pharmacists and scientists working in the Pharmacovigilance Group at the MHRA use the data to assess the causal relationship between the drugs and reported reactions, and to identify possible risk factors contributing to the occurrence of reactions, for example, age or underlying disease.

The data from the ADROIT database is available from the MHRA in the form of a Drug Analysis Printout (DAP). The DAP is not format or dose specific, but it provides a pattern of the adverse drug reactions experienced in the UK with ibuprofen.

A DAP printout for ibuprofen, covering the period 01/01/1992 - 31/12/2003 , shows there have been a total of 2014 suspected reactions reported in relation to all oral doses of ibuprofen, in prescription and non-prescription use.

Of the 2014 reported reactions only 5 were of Stevens-Johnson Syndrome, which accounts for a total of 0.25% of all reactions.

Of the 2014 reported reactions only 2 were of Epidermal Necrolysis, which accounts for a total of 0.10% of all reactions.

Of the 2014 reported reactions only 3 were of Erythema Multiforme, which accounts for a total of 0.15% of all reactions.

There were no specific reports for Lyell's syndrome.

Therefore EM/SJS and EN have a frequency of approximately 0.50% of all suspected reactions reported, which is lower than the prevalence suggested by the Halpern report. This is encouraging news bearing in mind the recently increased availability of ibuprofen, which was approved as a GSL or General Sales List product in the UK in 1996. This means the product has been deemed sufficiently safe to be sold without pharmaceutical supervision and can be obtained from many retail outlets such as supermarkets, newsagents and petrol stations.

To put the incidence of all reported undesirable effects into context, approximate sales volume figures for ibuprofen in the UK alone were in excess of 14 billion units for the same time period. This demonstrates the number of undesirable effects reported for ibuprofen is extremely low, particularly when compared with sales volume of ibuprofen, with EM/SJS and EN representing 0.50% of this number.

In conclusion, the reported side effects such as Stevens-Johnson Syndrome are rarely reported in context with ibuprofen - causality is not proven.   Incidence is in single cases only.  

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