Medications and illicit drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in THE MANUAL and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity syndrome, serum sickness, exfoliative dermatitis, angioedema, anaphylaxis, and medication-induced vasculitis.
Medications can also be implicated in hair loss, lichen planus, erythema nodosum, pigmentation changes, systemic lupus erythematosus, photosensitivity reactions, pemphigus, and pemphigoid.
Other medication and drug reactions are classified by lesion type.
Symptoms and Signs of Drug Eruptions and Reactions
Symptoms and signs vary based on the cause and the specific reaction (see table Types of Drug Reactions and Typical Causative Agents).
Urticarial lesions (wheals or hives) are migratory, elevated, pruritic, reddish plaques caused by local dermal edema.
Photo provided by Thomas Habif, MD.
This photo shows acneiform rash on the chest caused by corticosteroid treatment.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
This photo shows a morbiliform eruption secondary to use of a medication.
Photo courtesy of Anar Mikailov, MD, FAAD.
This photo shows a dusky purple plaque with slight erythema and scale at the periphery.
Photo courtesy of Karen McKoy, MD.
Urticarial lesions (wheals or hives) are migratory, elevated, pruritic, reddish plaques caused by local dermal edema.
Photo provided by Thomas Habif, MD.
This photo shows acneiform rash on the chest caused by corticosteroid treatment.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
This photo shows a morbiliform eruption secondary to use of a medication.
Photo courtesy of Anar Mikailov, MD, FAAD.
This photo shows a dusky purple plaque with slight erythema and scale at the periphery.
Photo courtesy of Karen McKoy, MD.
Types of Drug Reactions and Typical Causative Agents
Type of Reaction | Description and Comments | Typical Causative Agents |
|---|---|---|
Acneiform eruptions | Resemble acne but lack comedones and usually begin suddenly | Corticosteroids, epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MEK) inhibitors, halogens (eg, iodides, bromides), hydantoins, androgenic steroids, lithium, isoniazid, phenytoin, phenobarbital, vitamins B2, B6, and B12 |
Acute generalized exanthematous pustulosis | Rapidly appearing and spreading pustular eruption | Mainly antibiotics but some other medications |
Blistering eruptions | Appear with widespread vesicles and bullae | Pemphigus: Antibiotics, penicillamine, and other thiol compounds (including antihypertensives) Bullous pemphigoid: Penicillamine and furosemide (most common), immune checkpoint inhibitors, typically PD-1 inhibitors Linear immunoglobulin A (IgA) bullous dermatosis: Vancomycin (most common) |
Cutaneous necrosis | Appears as demarcated, painful, erythematous or hemorrhagic lesions progressing to hemorrhagic bullae and full-thickness skin necrosis with eschar formation | Warfarin, heparin, barbiturates, epinephrine, norepinephrine, vasopressin, levamisole (contaminant in street preparations of cocaine |
Appears as lupus-like syndrome, although often without the rash | Procainamide, minocycline, hydralazine, anti-tumor necrosis factor (TNF) medications, penicillamine, isoniazid, quinidine, interferon, methyldopa, chlorpromazine | |
Drug reaction with eosinophilia and systemic symptoms or drug hypersensitivity syndrome | Manifests as fever, facial edema, and rash 2–6 weeks after first dose of a medication Patients may have elevated eosinophils, atypical lymphocytes, hepatitis, pneumonitis, lymphadenopathy, and myocarditis Thyroiditis can be a sequela | Antiseizure medications, allopurinol, sulfonamides, minocycline, vancomycin Immune checkpoint inhibitors† |
Flagellate dermatitis | Linear erythematous wheals | Bleomycin and other antineoplastic agents |
Characterized by tender erythematous nodules, predominantly in the pretibial region, but occasionally involving the arms or other areas | Sulfonamides, oral contraceptives, penicillin, halogens (eg, bromides, iodides) | |
Exfoliative dermatitis/erythroderma | Characterized by erythema and scaling of the entire skin surface May be fatal | Antibiotics, antiseizure medications, antihypertensives, many others |
Fixed drug eruptions | Appear as frequently isolated, well-circumscribed, circinate or ovoid dusky red or purple lesions on the skin or mucous membranes (especially of the genitals) and reappear at the same sites each time the medication is taken | Antibiotics, NSAIDs, acetaminophen, barbiturates, antimalarials, antiseizure medications |
Lichenoid or lichen planus–like eruptions | Appear as angular papules that coalesce into scaly plaques | Angiotensin-converting enzyme inhibitors, beta-blockers, methyldopa, quinidine, thiazides, penicillamine, quinacrine Immune checkpoint inhibitors† |
Morbilliform or maculopapular eruptions (exanthems) | Most common hypersensitivity drug reaction Mildly pruritic, typically appearing 3 to 7 days after start of the medication | Almost any medication (especially barbiturates, analgesics, sulfonamides, ampicillin, and other antibiotics) |
Mucocutaneous eruptions | Vary from a few small oral vesicles or urticaria–like skin lesions to painful oral ulcers with widespread bullous skin lesions (see Erythema Multiforme and Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis) | |
Palpable purpura | Nonblanching purpuric papules most commonly on the lower extremities | Antibiotics, NSAIDs, antihypertensives, antiseizure medications, allopurinol |
Phototoxic reactions: Occur after direct damage of the tissue by exposure to the sunlight and medication and occur shortly after exposure and can look like a burn, including blistering; eruptions limited to sun-exposed skin Photoallergic reactions: Cell-mediated, can occur later, often with skin changes similar to those of eczema, and can spread to nonexposed skin | Medications that can cause phototoxic or photoallergic reactions: NSAIDs, chlorpromazine, phenothiazines, and sulfonamides Medication that tend to cause only phototoxic reactions: Antibiotics (eg, tetracyclines, fluoroquinolones) | |
Serum sickness–type drug reaction | A type III immune complex reaction Acute urticaria and angioedema more common than morbilliform or scarlatiniform eruptions Possibly polyarthritis, myalgias, polysynovitis, fever, and neuritis | Penicillin, insulin, foreign proteins |
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) | Characterized by focal areas of dusky red lesions, skin pain, and epidermal detachment of < 10% of BSA in SJS and > 30% of BSA in TEN* Skin and mucosa are involved; lips can develop hemorrhagic crusts and ulcerations Severe forms resemble staphylococcal scalded skin syndrome, a staphylococcal toxin–mediated disorder that occurs in infants, young children, and patients with immunosuppression May be fatal | Antiseizure medications, NSAIDs, penicillin, sulfonamides, antiretroviral medications Immune checkpoint inhibitors† |
Common Classically but not always IgE-mediated Easily recognized by typical well-defined edematous wheals May be accompanied by angioedema or other manifestations of anaphylaxis Occasionally the first sign of impending serum sickness, with fever, joint pain, and other systemic symptoms developing within days | NSAIDs can worsen urticaria, and urticaria can be a sign of many other drug reactions. | |
* When epidermal detachment occurs on 10 to 30% of BSA, the term SJS/TEN overlap is used. | ||
† Risks are highest with combinations of immune checkpoint inhibitors. When only single agents are used, risks are highest with inhibitors of CTLA-4, followed by inhibitors of PD1, then inhibitors of PD-L1. | ||
BSA = body surface area; CTLA-4 = cytotoxic T lymphocyte-associated antigen 4; NSAIDs = nonsteroidal anti-inflammatory drugs; PD-1 = programmed death receptor 1; PD-L1 = programmed cell death ligand 1; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis. | ||
Immune checkpoint inhibitors commonly cause drug eruptions or cutaneous symptoms (1). The most common are the following:
Less common examples include the following:
Psoriasiform dermatoses
Drug reaction with eosinophilia and systemic symptoms
Risks are highest with combinations of immune checkpoint inhibitors. When only single agents are used, risks are highest with inhibitors of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), followed by inhibitors of programmed death receptor 1 (PD1), then inhibitors of programmed cell death ligand 1 (PD-L1).
Symptoms and signs reference
1. Quach HT, Johnson DB, LeBoeuf NR, Zwerner JP, Dewan AK. Cutaneous adverse events caused by immune checkpoint inhibitors. J Am Acad Dermatol. 2021;85(4):956-966. doi:10.1016/j.jaad.2020.09.054
Diagnosis of Drug Eruptions and Reactions
Clinical evaluation and drug exposure history
Sometimes skin biopsy
A detailed history is often required for diagnosis, including recent use of over-the-counter medications and illicit drugs. Because the reaction may not occur until several days or even weeks after first exposure to a medication, it is important to consider all new medications and not only the one that has been most recently started.
No laboratory tests reliably aid diagnosis, although biopsy of affected skin is often suggestive.
Sensitivity can be definitively established only by rechallenge with the agent, which may be hazardous and unethical in patients who have had severe reactions. Occasionally, patch testing can be helpful in patients with fixed drug eruptions.
Treatment of Drug Eruptions and Reactions
Discontinuation of offending medication
Sometimes antihistamines and corticosteroids
Most drug reactions resolve when medications are stopped and require no further therapy. Whenever possible, chemically unrelated compounds should be substituted for suspect medications. If no substitute medication is available and if the reaction is a mild one, it might be necessary to continue the treatment under careful watch despite the reaction.
Pruritus and urticaria can be controlled with oral antihistamines and topical corticosteroids. For IgE-mediated reactions (eg, urticaria), desensitization can be considered when there is critical need for a medication.
Key Points
Because medications can cause a wide variety of reactions, medications should be considered as causes of almost any unexplained skin reaction.
Base the diagnosis primarily on clinical criteria, including a detailed history of prescription and over-the-counter medications.
Stop the suspected offending agent and treat symptoms as needed.
