Drug-Induced Rash: More Common Than You Think

Rashes caused by medication reactions are a common and sometimes serious condition.

Describing drug-induced skin rashes is like recounting stories about show dogs. It's almost impossible since the various dog breeds—like various drug types—have different presentations. Similarly, as dogs from the same breed can appear differently, so can rashes caused by the same drug. Regardless, pharmacists need to be aware of the high prevalence of drug-induced rash—rashes are the most common drug reaction reported—and around 30 patterns have been described.^1,2 Almost all drugs, especially antibiotics and NSAIDs,² have been associated with rash. Pharmacists should be able to differentiate between rashes that are more bark than bite and those that truly are aggressive.

Dog shows categorize dogs into companion, guardian, gundog, herding, hound, pastoral, scenthound, sporting, terrier, toy, and working groups. This article categorizes drug-induced rashes into similar groups—you’ll be surprised at the similarities.

Common Rashes

Table 1. Drugs Associated with Fixed Drug Eruption

Acetaminophen

Allopurinol

Antibiotics, particularly erythromycin, the penicillins, the tetracyclines, and sulfonamides

Barbiturates

Carbamazepine

Griseofulvin

Metronidazole

NSAIDs, including aspirin and coxibs

Paclitaxel

Phenolphthalein

Pseudoephedrine

Rifampin

Sulphonamides

Adapted from references 1, 3, and 9.

When we think of hounds, most of us hear that unique baying sound or Elvis’s croon, “You ain’t nothing but a hound dog!” In this rash category, let’s place commonly occurring, annoying, and frequently self-limiting rashes.

Simple exanthematous (which simply means blossoming) eruptions are the most common drug-induced rash, accounting for approximately 95% of skin reactions.^1,3 They are also called morbilliform (resembling measles) or maculopapular (with discoloration and raised bumps). Simple exanthems are itchy erythematous changes with no blisters or pus.

Starting on the trunk, exanthems typically spread peripherally and symmetrically within 1 week of initiation of the causative drug. They resolve within 7 to 14 days, fading from bright to brownish red, and may also end with scaling or desquamation. Common causes include penicillins, sulfonamides, nonnucleoside reverse transcriptase inhibitors (eg, nevirapine), and anti-epileptic medications. These reactions are mostly just a nuisance, although less than 2% may include fever and organ involvement.^1,3,4 The likelihood of examthematous reaction is quite high in 2 patient groups: those who have mononucleosis and take ampicillin (60%), and HIV-positive patients who take sulfonamides (50%).^5,6

Fixed drug eruptions (FDEs) also fit in the hound category—these, too, are annoying and self-limiting. FDE is an allergic rash that returns in the same place or places each time the drug is taken. It’ s usually well demarcated, occurring in round or oval raised or blistering patches. Burning, stinging, fever, malaise, and abdominal symptoms are possible. Starting with hyperpigmented red coloration, FDEs may fade to that shade dermatologists dub “violicious”—a purplish brown. Most FDEs develop on the genitals, perianal flesh, or extremities. FDEs usually occur 8 to 16 hours later, but can develop as early as 30 minutes after ingestion of the medication. On rechallenge with the offending agent, the lesions recur in the same location and often appear in new places.^1,7,8

Drug-Induced Rashes

Companion dogs are those cute little fluffballs that love to yap and cuddle. Companion rashes, on the other hand, are those that frequently accompany some drug therapies. For example, acne or acneiform reactions can be expected to develop or worsen when certain drugs are prescribed. These include the androgenic steroids, azathioprine, corticosteroids, danazol, granulocyte-stimulating factors, infliximab, iodides, lamotrigine, lithium, and tacrolimus.^1,3,10 In cases of an acne or acneiform rash in which the offending agent cannot be discontinued, topical tretinoin may be useful.^1,3 Prepubertal children do not develop acneiform eruptions, which suggests hormonal priming is a necessary prerequisite.^1,11

Another rash that seems to be a companion to certain drugs is Sweet Syndrome (SS or acute febrile neutrophilic dermatosis), a drug-induced vasculitis. In addition to well-demarcated papules and plaques that have dense neutrophilic infiltrates and are tender and erythematous, patients also experience sudden onset fever and leukocytosis. SS occurs in a small number of patients who take granulocyte colony or granulocyte-macrophage stimulating factors. SS often responds to prednisone. Other drugs associated with drug-induced vasculitis are propylthiouracil, hydralazine, allopurinol, cefaclor, minocycline, penicillamine, phenytoin, isotretinoin, and vaccines.^12,13

Persistent Rashes

Table 2. Drugs Often Associated with DRESS

Abacavir

Allopurinol

Aromatic anticonvulsants (barbiturates, carbamezepine, phenytoin)

Dapsone

Lamotrigine

Minocycline

Sulfonamides

Zalcitabine

DRESS = Drug Reactions (or Rashes) with Eosinophilia and Systemic Symptoms

Adapted from references 1, 3, 14, and 15.

Small but brazen, terriers are known for their noisy persistence. The quintessential terrier cartoon shows this dog chasing a squirrel and jumping so high it appears to climb a tree—long after the squirrel is out of its reach. In the terrier group, let’s put a persistent syndrome—Drug Reactions (or Rashes) with Eosinophilia and Systemic Symptoms (DRESS). This severe idiosyncratic drug reaction has a long onset latency, sometimes extending 2 to 8 weeks following exposure to an offending agent. It begins with wide- spread rash, but can progress to internal organ involvement, hematologic abnormalities, and systemic illness. It lasts longer than other drug-induced rashes after the drug is discontinued.^14,15

DRESS recurs with rechallenge. Patients who react to phenytoin, carbamazepine, and barbiturates will often cross-react to other aromatic anticonvulsants.^14,15

Reactivation of herpes viruses, especially of herpes virus 6, occurs frequently in this syndrome. DRESS can progress to a serious condition, especially in patients who have hepatitis.^1,14

Stopping the offending agent immediately, using systemic with tapering over 8 to 12 weeks, and topical, high-potency glucocorticoids can help.^1,14,15

Quality of Life

Working dogs are the canine muscle group: Malamutes, Portuguese Water Dogs, Saint Bernards, and Bernese Mountain Dogs. Often they are considered gentle giants. In the working rashes group, we can include rashes caused by the epidermal growth factor receptor (EGFR) inhibitors cetuximab, erlotinib, gefitinib, and panitumumab. While they aren’t necessarily gentle, they are giants among rashes.

EGFR inhibitors are used in a variety of cancers with good results. Most patients, however, develop a papulopustular acneiform rash in cosmetically sensitive areas (scalp, face, upper chest, and back) during the first 2 months of therapy. This can decrease quality of life.^16,17 There’ s another reason why we can put EGFR inhibitors in the “working” group. Increasingly, it is becoming apparent that if the patient develops this drug-induced rash, the drug is working.

Early clinical investigators noticed an apparent correlation between the development of rash, increasing rash severity, and tumor response to this antineoplastic treatment. While there is still minor controversy surrounding this issue, it seems likely that developing a rash is associated with better survival rates. Oncologists have used the probable correlation as motivation to encourage adherence even if skin involvement is extensive. Additionally, topical hydrocortisone 1% cream, sunscreen-containing moisturizers, systemic minocycline or doxycycline, and/or low-dose isotretinoin have been helpful.^1,16,17

Dangerous Rashes

Although rare, some dogs bite and must be kept away from strangers (both human and dog). Whether this issue stems from their breed’s innate propensity to protect, or training by their owners that encourages aggression, is controversial. Likewise, some drug-induced rashes are dangerous, requiring emergency care, and their causes may be genetic, idiosyncratic, or controversial.

Patients sometimes visit the pharmacist when a rash starts to develop. Four basic questions will need to be answered:

• Is it a drug reaction?
• Which drug is suspected, and should it be discontinued immediately?
• Is it a severe rash or a rash that may become severe?
• Where should the patient be referred?^1,3

Table 3. Pharmaceutical Care for Drug-Induced Rash

• Take a detailed medication history, including OTC preparations, herbal and naturopathic remedies. Pay special attention to new drugs started within the preceding 6 weeks
• Tell the patient to stop taking the drug and send the patient for emergency care if: The rash is extensive, painful, purpural, necrotic, involves the face or mucous membranes or causes tongue swelling The patient has fever >104°F, arthralgias, shortness of breath, wheezing, or hypotension
• If the rash seems to be less extensive or of the self-limiting, annoying type, refer the patient to his or her prescriber—it’s important to have drug-induced rash assessed and recorded in the patient’s medical record

Adapted from references 3 and 14.

Conclusion

Most, but not all, drug-induced rashes occur with the first exposure to an agent. Most are benign.^1,3,14 Some drugs tend to cause rash more frequently than others. Being aware of the most likely groups of rashes can help pharmacists refer patients quickly and appropriately. Once the causative agent is identified, patients can begin to heal.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance clinical writer.

References

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• Jappe U. Amoxicillin-induced exanthema in patients with infectious mononucleosis: allergy or transient immunostimulation? Allergy. 2007;62:1474-1475.
• Wargo KA, McConnell V, Jennings M. Amoxicillin/telithromycin-induced rash in infectious mononucleosis. Ann Pharmacother. 2005;39:1577.
• Wei CY, Ko TM, Shen CY, Chen YT. A recent update of pharmacogenomics in drug-Induced severe skin reactions [published online 2011]. Drug Metab Pharmacokinet.
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• Hurwitz RM. Steroid acne. J Am Acad Dermatol. 1989;21:1179-1181.
• Knowles S, Shapiro L, Shear NH. Drug eruptions in children. Adv Dermatol. 1999;14:399-415.
• Bidyasar S, Montoya M, Suleman K, Markowitz AB. Sweet syndrome associated with granulocyte colony-stimulating factor. J Clin Oncol. 2008;26(26):4355-4366.
• Thompson DF, Montarella KE. Drug-induced Sweet’s syndrome. Ann Pharmacother. 2007;41:802-811.
• Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331:1272-1285.
• Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588-597.
• Lacouture ME, Anadkat MJ, Bensadoun RJ, et al; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011;19:1079-1095.
• Oishi K. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncol Nurs Forum. 2008;35:103-111.