What it is:The skin is the organ that shows drug reactions the most often, and the reactions range from "annoying rash you can outlast" to "call an ambulance." Same chapter also covers three non-drug skin conditions you'll see constantly in practice: contact dermatitis, diaper dermatitis, and atopic dermatitis.
The core problem:Most drug rashes look similar at first glance (red, spreading, itchy), but a handful of them are actually severe cutaneous adverse reactions (SCARs) that kill people if you miss them. The entire skill here is pattern recognition: what does it look like, and is there fever or organ involvement riding along with it.
What you do about it:Stop the suspected drug immediately, control symptoms, and know which four red flags mean this isn't a simple rash anymore.
Organize every drug eruption around two questions: (1) what's the morphology(exanthematous, urticarial, blistering, or pustular) and (2) is there fever or systemic involvement.The exact same starting category has a benign version and a dangerous version, and fever is usually what separates them. A maculopapular rash without fever is a nuisance; the same rash with fever, lymphadenopathy, and organ involvement is DRESS. That single framework carries you through this whole chapter.
DiPiro organizes cutaneous drug eruptions into four morphologic buckets, and each one branches into a "no fever" version and a "with fever" version. Learn the branch, not just the bucket.
| Morphology | Without fever / systemic signs | With fever / systemic signs |
|---|---|---|
| Exanthematous | Simple maculopapular eruption | DRESS(drug reaction with eosinophilia and systemic symptoms) |
| Urticarial | Urticaria / angioedema | Serum sickness-like reaction |
| Blistering | Fixed drug eruption / bullous eruption | SJS/TEN(Stevens-Johnson syndrome / toxic epidermal necrolysis) |
| Pustular | Acneiform eruption | AGEP(acute generalized exanthematous pustulosis) |
SJS/TEN, DRESS, and AGEP are collectively the SCARs(severe cutaneous adverse reactions). They aren't separate diseases from the "mild" version in their row, they're the same starting morphology plusfever and systemic involvement. If a patient has a blistering rash and a fever, you should already be thinking SJS/TEN, not "bad fixed drug eruption."
Drug-induced skin reactions are either irritant(direct chemical damage, no immune system needed) or allergic(an immunologic response to the drug or a metabolite). The allergic ones are what get sorted into the four morphologic families above.
Phototoxic looks like an exaggerated sunburn, happens on the first exposure, and is dose-dependent. Photoallergic looks eczematous, needs a prior sensitizing exposure, and can spread beyond the sun-exposed area. If a patient says "I've taken this medication for years and now suddenly I'm reacting to the sun," that pattern fits photoallergic, not phototoxic.
Timing and morphology are your two biggest clues. Onset relative to starting the drug is often the single most useful data point you'll get from the history.
| Reaction | Onset | What you see | Usual culprits |
|---|---|---|---|
| Maculopapular (exanthematous) | 7–10 days after starting | Erythematous macules/papules, may be pruritic, can spread and become confluent. Resolves 7–14 days after stopping the drug. | Penicillins, cephalosporins, sulfonamides, some anticonvulsants |
| DRESS | 1–4 weeks | Exanthem + fever + lymphadenopathy + multiorgan involvement (kidney, liver, lung, bone marrow, heart, brain). Can be fatal if not treated promptly. | Allopurinol, sulfonamides, anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrigine), dapsone |
| Urticaria / angioedema | Minutes to hours | Extremely pruritic red raised wheals, angioedema, mucous membrane swelling. Can be the first sign of anaphylaxis. | Penicillins, aspirin, sulfonamides, radiograph contrast media, opioids |
| Serum sickness-like reaction | 1–3 weeks | Fever + urticarial rash + arthralgias, a "complex" urticarial presentation | - |
| Fixed drug eruption | Minutes to days; recurs at the same siteevery time the drug is re-given | Pruritic, red, raised lesions that may blister; burning or stinging; leaves hyperpigmentation for months after it clears | Tetracyclines, barbiturates, sulfonamides, codeine, phenolphthalein, NSAIDs |
| SJS/TEN | 7–14 days | Tender/painful bullae, fever, headache, respiratory symptoms, rapid confluence and spread with extensive epidermal detachment/sloughing. Fluid loss, hypotension, electrolyte imbalance, secondary infection follow. | Sulfonamides, penicillins, anticonvulsants (hydantoins, carbamazepine, barbiturates, lamotrigine), NSAIDs, allopurinol |
| Acneiform eruption | 1–3 weeks | Pustular, acne-like eruption | Corticosteroids, androgenic hormones, some anticonvulsants, isoniazid, lithium |
| AGEP | Acute, within days | Fever, diffuse erythema, many pustules. Generalized desquamation follows about 2 weeks later. | β-lactam antibiotics, macrolides, calcium channel blockers |
Maculopapular reactions take 7–10 days to show up. That means a patient can finish a 7-day antibiotic course and stop it entirelybefore the rash even appears. Don't let the rash-after-the-drug-was-stopped timing fool you into ruling out that antibiotic as the cause.
Sun-induced reactionslook like an exaggerated sunburn: erythema, papules, edema, sometimes vesicles, confined to sun-exposed skin (ears, nose, cheeks, forearms, hands). Diaper dermatitispresents as erythematous rash in the covered area; severe cases show vesicles and oozing erosions, and a superimposed Candida infection presents with confluent red plaques, papules, and pustules.
There's no single lab test for "this is a drug rash." Diagnosis is built from a careful history plus a systematic look at the lesions themselves.
Identify the lesion type: macules, papules, nodules, blisters, plaques, lichenification. Many conditions produce more than one lesion type at once, so don't force it into a single category. Inspect for color, texture, size, and temperature, since areas that are oozing, erythematous, and warm to the touch may be secondarily infected.
Goals of treatment:relieve bothersome symptoms, remove the precipitating factor, prevent recurrence, avoid adverse effects from the treatment itself, and improve quality of life.
If a drug-induced skin reaction is suspected, discontinue the suspected drug as quickly as possibleand avoid potential cross-sensitizers. Everything else is downstream of this. The longer the offending drug stays on board, the worse the reaction gets.
Tell the patient exactly which drug is suspected, which related drugs to avoid going forward, and what they can take instead. For photosensitivity reactions specifically, add sunscreen and sun avoidance counseling since re-exposure to sunlight (not just the drug) is what triggers the reaction.
SJS and TEN are considered variants of the same disorder along a severity spectrum and are usually discussed together as SJS/TEN. Both are rare but severe, life-threatening blistering reactions. DRESS is its own entity but shares the "fever plus multiorgan involvement" danger profile.
Once you're dealing with life-threatening SJS/TEN, this is a supportive-care emergency: maintain adequate blood pressure and fluid/electrolyte balance, give broad-spectrum antibiotics and vancomycinfor secondary infection, and consider IV immunoglobulin (IVIG). Corticosteroid use is controversial; if they're used, give relatively high doses initially and taper rapidly once disease progression stops.
Anticonvulsants show up in the SJS/TEN and DRESS culprit lists over and over, and the seizure disorders course material adds detail worth knowing drug-by-drug:
| Drug | SJS/TEN-relevant detail |
|---|---|
| Carbamazepine | Rash risk (including SJS/TEN) is markedly higher in HLA-B*1502 carriers, an allele more common in patients of Asian ancestry. This is why genetic screening is recommended before starting carbamazepine in at-risk populations. |
| Lamotrigine | Rash risk (including SJS/TEN) is minimized with slow titration. Valproate raises lamotrigine levels and rash riskby inhibiting its metabolism, so lamotrigine doses must be started lower and titrated more slowly when combined with valproate. |
| Phenytoin (a hydantoin) | Rash including SJS/TEN is a known adverse effect, alongside gingival hyperplasia, hirsutism, ataxia, and peripheral neuropathy. |
| Oxcarbazepine | Rare SJS/TEN risk, generally considered lower than carbamazepine. |
This is exactly why lamotrigine is titrated so slowlyin practice (small increases over weeks, even slower if combined with valproate). It isn't about seizure control at all, it's a strategy to minimize SJS/TEN risk. If you see a lamotrigine titration schedule on an exam, the "why" is rash prevention.
Don't anchor on anticonvulsants alone. Allopurinolis a major DRESS and SJS/TEN culprit. Sulfonamidesand penicillinshit almost every category in this chapter (maculopapular, DRESS, SJS/TEN), which is why a documented sulfa or penicillin allergy always deserves a closer look at what actually happened, not just a reflexive avoidance label.
Allergic contact dermatitis (ACD)is a true immune response to an antigenic substance, sometimes delayed several days after exposure. Irritant contact dermatitis (ICD)is caused by direct chemical/organic damage and usually shows up within a few hours.
| Step | What to do |
|---|---|
| 1. Identify and avoid | Identification, withdrawal, and avoidance of the offending agent comes first, every time. |
| 2. Symptomatic relief | Cold, wet compressesfor wet/oozing lesions: apply, remove, remoisten, reapply every few minutes for 20–30 minutes. Wet dressing soaks(no removal, up to 20–30 min) for dry/hardened lesions to soften and hydrate. Don't use soaks on acutely oozing lesions. Calamine lotion or Burow solution (aluminum acetate) can also soothe. |
| 3. Topical corticosteroids | The mainstay of treatment. ACD responds better than ICD. Start with higher potency, then step down to medium/lower potency as the condition improves. |
| 4. Adjuncts | Oatmeal baths or oral first-generation antihistamines for itch. Moisturizers to prevent dryness and fissuring. |
Refer if the rash doesn't respond after a week of treatment, if pain or inflammation increasesduring therapy, if ulcerations develop, or if there are systemic signs like fever, diarrhea, or skin lesions elsewhere on the body.
Presentation changes with age, which is a classic testable detail.
| Age | What it looks like |
|---|---|
| Infancy | Erythematous, patchy, pruritic, papular rash starting on cheeks and chin, progressing to red, scaling, oozing lesions. Affects the malar cheeks, forehead, scalp, chin, and behind the ears, while sparing the nose and paranasal creases. Over weeks, spreads to the extensor surfaces of the lower legs (from crawling), and eventually can involve the whole body except the diaper area and nose. |
| Childhood | Skin is dry, flaky, rough, cracked. Pruritus is a requiredfeature; you cannot diagnose AD without a history of itching. Scratching and rubbing causes bleeding and lichenification. |
| Adulthood | More diffuse lesions with underlying erythema. Face is commonly involved and may be dry and scaly. Lichenification may be present. |
Infantile AD spares the nose and paranasal creaseseven while covering the rest of the face, which is the opposite of what you might expect for a "facial rash." And remember, pruritus isn't just a symptom of AD, it's a diagnostic requirement. No itch, no AD diagnosis.
Topical corticosteroids are the drug treatment of choice in AD. Potency selection depends on body site, severity, and duration of use, not a one-size-fits-all strength.
| Situation | Potency | Example |
|---|---|---|
| Face | Low potency | Hydrocortisone 1% |
| Body | Medium potency | Betamethasone valerate 0.1% |
| Long-duration maintenance | Low potency | - |
| Short-term exacerbation management | Mid- to high-potency | - |
| Lichenified lesions in adults, 1–2 weeks only | Ultra-high / high potency | Betamethasone dipropionate 0.05%, clobetasone propionate 0.05% |
Avoid potent fluorinated corticosteroidson the face, genitalia, and intertriginous areas, and in infants. Once lichenified lesions improve, step back down to a lower-potency agent for maintenance.
Tacrolimus (Protopic)and pimecrolimus (Elidel)inhibit calcineurin, which normally kicks off T-cell activation. Both are approved for AD in adults and children over age 2.
Most common adverse effect is transient burning at the application site. Both are second-linedue to a possible cancer risk signal, which is why SPF 30+ on all exposed skin is recommended alongside them.
Coal tar preparations(crude coal tar, liquor carbonis detergens) have long history of use but weak trial support, plus they stain and smell. Avoid on acutely inflamed skin, since it can add irritation.
Crisaborole (Eucrisa) 2% ointmentis a PDE4 inhibitor approved for mild-to-moderate AD, ages 2 and up. Apply a thin layer BID. Burning or stinging at the site can occur.
Phototherapyis an option when topical corticosteroids and calcineurin inhibitors aren't controlling the disease. It can be steroid-sparing, letting you use lower-potency corticosteroids or sometimes none at all.
Dupilumab (Dupixent)is an IL-4 receptor alpha antagonist given SC, FDA approved for moderate-to-severe AD in patients 12 and older whose disease isn't adequately controlled with topical prescription therapy (or when topicals aren't advisable). Can be combined with topical corticosteroids. Topical calcineurin inhibitors may still be used with it, reserved for problem areas like the face, neck, intertriginous, and genital areas. Most common adverse reactions (≥1%): injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other HSV infection, dry eye.
Upadacitinib (Rinvoq)and abrocitinib (Cibinqo)are oral JAK inhibitors approved for refractory, moderate-to-severe AD not adequately controlled with other systemic drugs, including biologics. Upadacitinib is approved down to age 12; abrocitinib is adults only. Both carry a boxed warning for increased risk of serious infection, mortality, malignancy, major cardiovascular events, and thrombosis.
Other systemic options used off-label(not FDA approved for AD): other biologics, systemic corticosteroids, cyclosporine, interferon-γ, azathioprine, methotrexate, mycophenolate mofetil, IVIG.
| Drug | Start / dose | Notes |
|---|---|---|
| Topical (second-line) | ||
| Tacrolimus ointment 0.03% | BID | Ages 2–15, moderate-to-severe AD |
| Tacrolimus ointment 0.1% | BID | Ages 16+ |
| Pimecrolimus cream 1% | BID | Ages 2+, mild-to-moderate AD |
| Crisaborole 2% ointment | Thin layer BID | Ages 2+, mild-to-moderate AD |
| Biologic | ||
| Dupilumab, adult | 600 mg load (two 300 mg SC) then 300 mg SC every other week | Age 12+, moderate-to-severe |
| Dupilumab, 12–17y, <60 kg | 400 mg load (two 200 mg SC) then 200 mg SC every other week | Weight-based dosing |
| Dupilumab, 12–17y, >60 kg | 600 mg load (two 300 mg SC) then 300 mg SC every other week | Weight-based dosing |
| Oral JAK inhibitors boxed warning | ||
| Upadacitinib (Rinvoq) | 15 mg PO daily, up to 30 mg dailyif inadequate response | Age 12+, refractory disease |
| Abrocitinib (Cibinqo) | 100 mg PO daily, up to 200 mg dailyif no response | Adults only, refractory disease |
| Other reaction management | ||
| Prednisone (photosensitivity) | 1 mg/kg/day | Taper over 3 weeks |
| Hydrocortisone 0.5%–1% (diaper dermatitis) | Short course | 1–2 weeks only, severe inflammatory cases |
| Parameter | When | Watching for |
|---|---|---|
| Skin/lesion exam | Every visit during an acute drug reaction | Spread, new blistering, mucosal involvement (signals escalation toward SJS/TEN) |
| Vital signs | Whenever systemic signs are present (DRESS, SJS/TEN) | Fever, hypotension from fluid loss through denuded skin |
| CBC (with eosinophils), LFTs, renal function | Suspected DRESS | Eosinophilia, hepatic or renal involvement |
| Fluid and electrolyte status | SJS/TEN | Dehydration and electrolyte imbalance from epidermal fluid loss |
| Signs of secondary infection | Any blistering or denuded skin | Fever, purulent drainage, spreading warmth/erythema |
| AD severity / body surface area involved | Every AD visit | Flare control, whether to step therapy up or down |
| Eye exam | Patients on dupilumab | Conjunctivitis, blepharitis, keratitis (labeled adverse effects) |
| Infection screening | Before and during JAK inhibitor or dupilumab therapy | Serious infection risk, part of the JAK inhibitor boxed warning |
| Application site | Topical calcineurin inhibitors, crisaborole | Burning or stinging, the most common adverse effect |