Drug reaction fixe L27.1

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 10.12.2021

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Drug exanthema fixed toxic; Drug reaction fixed generalized bullous; FDE; Fixed drug eruption; Fixed drug exanthema; Fixed drug reaction; Fixed toxic drug exanthema; Fixed toxic drug reaction; GBFDE; Generalized bullous fixed drug eruption; Generalized bullous fixed drug exanthema

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Bourns in 1899; Brocq in 1894;

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Localized, spotty or plaque shaped, also bullous or erosive drug reaction,

  • which occurs in a temporal connection with the intake of drugs (triggering drugs see table) in therapeutic doses
  • is limited to a solitary stove or a few stoves
  • and
  • tends to recur in situ (recurrence in loco).

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The immunopathogenetic mechanism of the fixed drug reaction has not yet been clarified (see also under erythema exsudativum multiforme). The central role is played by CD8+ T cells which show a phenotype similar to the effector memory T cell and are mainly responsible for the epidermal damage. CD8+ positive cells persist for years in old, already clinically healed lesions(tissue-resident memory cells) and can be expressed and activated on keratinocytes after renewed exposure to the agent via a probably TNF-alpha induced upregulation of ICAM-1 (see below adhesion molecules) (see also UV reactivation reaction). The release of interferon gamma leads to an inflammatory reaction.

The apoptosis of the keratinocytes (which is clearly visible histologically) seems to be induced by a FAS-FAS ligand interaction (see below CD classification - CD95, or CD95L).

Of note is the role of viral infections (e.g., herpes simplex infections) as co-factors for the "recurrence" of the fixed drug response. A so-called recall reactivation reaction can be assumed for the recurrent "in-loco occurrence", although the immunological processes for this are also still unclear (see also under UV reactivation reaction).

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Occurrence 1-2 weeks after (first) use of the drug. With repeated ingestion, occurrence within 30 min. up to 24 hours possible. The relationship between drug intake and the appearance of the lesions is not always clear.

Occurrence possible in all age groups. Predominance between 20-60 years (average in larger studies at 36-53J). No gender predilection.

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Ubiquitous occurrence is possible.

Preference is given to the upper extremity (about 50%), followed by the lower extremity, lips, face, penis, vulva; involvement of the oral mucosa can occur very incisively (cheek mucosa, gingiva, hard and soft palate). The mucosa of the glans penis and vulva are also typical (often unrecognized) sites of manifestation.

Clinical features
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Solitary or restricted to a few foci, 2.0-5.0 cm large (more rarely up to 10 cm large plaques), round or oval (rarely also anular), initially deep red, later blue to brown-red, after healing brown (post-inflammatory hyperpigmentation), sharply defined, succulent, itchy or even slightly painful spots or plaques. Blistery transformation in the centre is possible. In the case of intertriginous infestation, diagnosis can be made more difficult because the characteristic clinical morphology is overlaid by local factors. Clinically impressive is then a (large) area erosion.

The generalised, possibly multilocular, bullous fixed drug reaction (GBFDE) is described as themaximum variant , which can occur in adults as well as in children.

An extreme intertriginous variant is the so-called " Baboon syndrome".

Upon re-exposure, the lesions reappear within 24 hours at exactly the same site. However, a refractory period can occur immediately after healing of the lesion.

A distinction must be made:

  • Classical fixed drug response: Most common form which heals by long-term persistent post-inflammatory hyperpigmentation.
  • Non-pigmented variant of the fixed drug reaction: Rarer form; generally occurs over a larger area (up to 10 cm in size) and heals without post-inflammatory hyperpigmentation.
  • Urticarial fixed drug reaction: Rare variant which recurs urticarially and in loco when provoked.
  • Neutrophilic fixed drug reaction: Extremely rare variant which histologically presents as neutrophilic dermatitis. Only few case reports have been published so far.

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Interface dermatitis with numerous apoptotic keratinocytes; lichenoid and perivascular inflammatory reaction of the upper and middle dermis; few eosinophil and neutrophil granulocytes. Indicated or pronounced papilledema up to subepidermal cleft or blister formation. Initially slight, later pronounced pigment incontinence.

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Clinical picture with recurrence in loco.

Note: Eye drops should also be considered during medical history!

The results of prick-scratch tests are evaluated differently. They are performed in loco in healed lesions. In individual studies (e.g. for non-steroidal anti-inflammatory drugs), reliable positive results of 40% are reported (Andrade 2011).

Oral provocation with the drug in question is the proof.

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Withdrawal of the suspected substance, depending on clinical presentation and extent, either wait-and-see or local glucocorticoids.

Internal therapy
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In case of corresponding severity of the clinical picture: systemic glucocorticoids in medium dosages, e.g. 60-80 mg prednisolone equivalent per day p.o. (e.g. Decortin ®).

Later gradual dose reduction, stomach protection. For severe pruritus antihistamines such as Dimetinden, e.g. Fenistil® 2 times/day 1 amp. i.v. or Desloratadin (Aerius®) 1 time / day 1 tbl. p.o.

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In larger collectives an average of 2.6 recurrences (1-10 recurrences) were anamnestized.

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Medication Group

Active ingredients

Classical form


Acetaminophen, acetylsalicylic acid, ibuprofen, indometacin, naproxen, phenazone derivatives, paracetamol, sulindac


carbamazepine, lorazepam, lormetazepam (noctamide), oxazepam, temazepam

Antihistamines (H1 blockers)

Cetirizine, dimenhydrinate, hydroxyzin hydrochloride (Atarax), loratadine

Antimicrobially active substances

amoxycillin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, ketoconazole, metronidazole, minocycline, norfloxacin, ofloxacin, penicillin, rifampicin, terbinafine, tetracyclines, trimethoprim-sulfamethoxazole, vancomycin

COX-2 inhibitors

Celecoxib, parecoxib, valdecoxib

Local anaesthetics

Articaine, lidocaine, mepivacaine


Aciclovir, allopurinol, atenolol, barbiturates, BCG vaccine, benzodiazepines, chloroquine, clioquinol, dapsone, foscarnet, dextromethorphan, diflunisal, dimenhydrinate (Volon A), docetaxel, influenza vaccine, heparin, interferon-ribavirin combinations, interleukin-2, iopamidol (contrast medium), Kakkon-To (Japanese medicinal plant), lactose (z.B. in botulinum preparations), magnesium, omeprazole, oral contraceptives, melatonin, metamizole, ondansetron (Zofran), paclitaxel, pyrimethamine sulfadoxins (fansidar), quinolones, sulfasalazine, sulfaguanidine, ticlopidine, tolmetin, tosufloxacintosilate, triamcinolone, tropisetron, tropotecan (hydrogenzamtin)

Non-pigmented variant

betahistine (antiemetic), cimetidine, ephedra heba ("ma huang"), ephedrine, paracetamol, piroxicam, pseudoephedrine, tetrahydrozoline, triamcinolone acetonide

Case report(s)
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Medical history: A 67-year-old patient reported a treatment with Terbinafine because of a therapy-resistant onychomycosis. 2 hours after taking the 1st tablet he had noticed strongly itchy wheals on the inner side of the right upper arm. The treatment was then discontinued. The symptoms had receded.

Diagnosis: Epicutaneous and prick tests with Terbinafine o.B. When provoking the drug orally (125 mg Terbinafine) the patient developed an itchy wheal field of 6x6 cm on the inner side of the right upper arm within 3 hours. Testing was discontinued; the patient received symptomatic therapy with prednisolone and clemastine. Below this the symptoms improved within a few hours.

Diagnosis: Fixed (urticarial) drug reaction.

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.


Last updated on: 10.12.2021