Does hydroxyzine cause skin rashes?

Does Hydroxyzine Cause Rashes?

Yes, hydroxyzine can paradoxically cause skin rashes, though this is rare—it may worsen the very dermatologic conditions it is prescribed to treat, particularly in patients with ethylenediamine sensitivity or piperazine cross-reactivity.

Mechanism and Incidence

• Hydroxyzine rarely induces allergic hypersensitivity reactions, primarily linked to its piperazine-derivative structure based on ethylenediamine 1
• The FDA warns that hydroxyzine may rarely cause Acute Generalized Exanthematous Pustulosis (AGEP), a serious skin reaction characterized by fever and numerous small, superficial, sterile pustules arising within large areas of edematous erythema 2
• Systemic administration of antihistamines rarely induces allergic reactions compared to topical application, but when it occurs, it is mainly linked to phenothiazine-derived and piperazine-derived compounds like hydroxyzine 1

Clinical Presentations of Hydroxyzine-Induced Rashes

Morbilliform Eruptions

• Generalized morbilliform rashes with pruritus can develop after hydroxyzine administration, sometimes progressing to complete desquamation 1, 3
• These eruptions may appear shortly after the initial dose, even in patients taking hydroxyzine for the first time, suggesting prior systemic sensitization 4

Fixed Drug Eruption

• Fixed drug eruption of the penis has been documented in children treated with hydroxyzine for restlessness, with positive macrophage migration inhibiting factor (MIF) assay confirming the diagnosis 5

Contact Dermatitis Exacerbation

• Hydroxyzine can worsen existing contact dermatitis in ethylenediamine-sensitive patients, causing papulovesicular eruptions despite being prescribed to treat pruritus 6
• Patch testing may reveal positive reactions to hydroxyzine, ethylenediamine dihydrochloride, and related compounds 6

Cross-Reactivity Patterns

• Cross-reactivity with cetirizine is well-documented, as both are piperazine derivatives structurally based on ethylenediamine 1, 3
• The FDA explicitly recommends avoiding cetirizine or levocetirizine in patients who have experienced AGEP or other hypersensitivity reactions with hydroxyzine due to cross-sensitivity risk 2
• Oral challenge tests with both cetirizine and hydroxyzine can reproduce identical cutaneous reactions in sensitized patients 3

Critical Diagnostic Approach

When to Suspect Hydroxyzine as the Culprit

• Any worsening of skin lesions after starting hydroxyzine should raise suspicion, as antihistamines are often not recognized as the cause of cutaneous eruptions 1, 4
• Look for bilateral palmar erythema evolving to generalized morbilliform rash with desquamation 1
• Consider hydroxyzine-induced rash if symptoms appear within days of initiation, even in first-time users 4

Diagnostic Testing

• Perform patch testing (read at 48 and 96 hours) with hydroxyzine and related antihistamines 1
• Patch tests with ethylenediamine dihydrochloride help identify cross-reactivity 6
• Controlled oral challenge tests can confirm the diagnosis but should only be performed in supervised settings 1
• Skin prick and intradermal tests are typically negative, making patch testing more reliable 1

Management Algorithm

Immediate Actions

• Discontinue hydroxyzine immediately at the first appearance of skin rash, worsening of pre-existing skin reactions, or any sign of hypersensitivity 2
• If signs or symptoms suggest AGEP (fever, pustules, edematous erythema), hydroxyzine should not be resumed and alternative therapy must be considered 2
• Seek medical evaluation right away, particularly if accompanied by blistering, mucosal involvement, or systemic symptoms 7

Alternative Antihistamine Selection

• Switch to non-piperazine antihistamines such as dexchlorpheniramine, which typically do not cross-react 1
• Avoid cetirizine and levocetirizine permanently due to documented cross-sensitivity 2
• Second-generation non-sedating antihistamines (loratadine, fexofenadine) are safer alternatives for daytime use 8

Common Pitfalls to Avoid

• Do not assume worsening dermatitis is disease progression—always consider hydroxyzine as a potential cause when skin conditions deteriorate during treatment 1, 4
• Do not rechallenge with hydroxyzine if hypersensitivity is suspected; use alternative antihistamines instead 2
• Do not overlook ethylenediamine sensitivity—patients with contact dermatitis to ethylenediamine-containing products are at higher risk 6
• Do not prescribe cetirizine as an alternative in patients with confirmed hydroxyzine hypersensitivity due to structural similarity and cross-reactivity 2, 3