FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen

By Effective Medicine  On  In Drugs Tagged ,  

Data Summary

FDA reviewed the FDA Adverse Event Reporting System (FAERS) database and the medical literature for evidence of an association between acetaminophen and Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).  The evidence supporting causality between acetaminophen and serious skin reactions primarily comes from a small number of published cases in which patients were rechallenged with acetaminophen and had a recurrence of a serious skin reaction.1-3

  • In one case, a 7-year-old girl with fever and sore throat was treated with three doses of acetaminophen (10 mg/kg), and 12 hours later, she developed an erythematous rash over her gluteal region and legs.  Her condition worsened, and she was admitted to a hospital.  Her skin biopsy was compatible with TEN.  Six months later, an allergist questioned the diagnosis of TEN due to acetaminophen and performed an oral rechallenge with acetaminophen 250 mg.  No other drugs were used.  Thirty minutes later, the patient developed diffuse urticaria and erythema and was readmitted to the hospital.1  
  • In another case, an 11-year-old boy was hospitalized for SJS.  He had taken acetaminophen for a cold and presented to medical attention with malaise, fever, and erythematous macules that progressed to erosive, hemorrhagic lesions.  Laboratory testing included a biopsy that was compatible with SJS.  A later oral test with acetaminophen (clinicians were unaware the original reaction was associated with acetaminophen) resulted in erythema multiforme, diagnosed clinically with a compatible biopsy.2  
  • In a third case, an 83-year-old man took acetaminophen and multiple other drugs for a hip replacement.  He was admitted to the hospital with an erythematous rash with hundreds of small, nonfollicular pustules; biopsy showed subcorneal pustules, spongiosis, papillary edema, and a perivascular infiltrate consistent with AGEP.  All drugs were stopped with resolution of the eruption and widespread desquamation.  Skin patch tests with acetaminophen only resulted in subcorneal pustules.  He experienced a recurrence of AGEP with subsequent administration of intravenous propacetamol, a prodrug of acetaminophen.3

In addition to the three positive rechallenge cases, the medical literature contained several cases of SJS, TEN, and AGEP (3, 17, and 6 cases, respectively) in which the only drug administered prior to the reaction was acetaminophen, or acetaminophen hypersensitivity was demonstrated by skin testing or other means.1-20  There were no deaths reported in the literature, but the majority of cases required hospitalization.  All cases resolved with discontinuation of the drug.

A search of FAERS from 1969 to 2012 identified 91 cases of SJS/TEN and 16 cases of AGEP, which resulted in 67 hospitalizations and 12 deaths.  The majority of the cases involved single-ingredient acetaminophen products.  A small number of cases involved injectable acetaminophen products or oral acetaminophen/opioid fixed-dose combination products.  Indications for acetaminophen use varied between pyrexia and analgesia, and the majority of the reported doses were consistent with labeled dosing recommendations.

Of the 91 cases of SJS/TEN, 6 were categorized as probable cases associated with acetaminophen, with the rest categorized as possible cases.  Of the 16 cases of AGEP, 1 was categorized as a probable case associated with acetaminophen, with the rest categorized as possible cases.  These seven probable cases had a confirmed diagnosis of SJS/TEN or AGEP by a dermatologist and/or histological findings temporally associated with acetaminophen; confounding medications were not administered within two weeks preceding the events.  The time to event, which was measured from the initiation of acetaminophen to the onset of cutaneous signs and symptoms, ranged from less than 24 hours to 8 days.  Among these probable cases, six people were hospitalized and one died.

FDA’s review of five SJS/TEN case-control studies and one of AGEP indicated that risks of SJS/TEN may be increased with the use of acetaminophen and were generally independent of the effects of other drugs.21-26  However, all but two of these case control studies failed to address the possible presence of protopathic bias, which in this setting refers to a false increase in the risk of SJS/TEN attributable to acetaminophen, due to its use to treat fever, a prodromal symptom of SJS/TEN.  In one of the two studies that controlled for the confounding effect of protopathic bias by limiting the acetaminophen exposure period to a time preceding the prodromal period, acetaminophen remained significantly associated with SJS/TEN.26

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