Which of the following medications, Dapagliflozin, Eplerenone, Apixaban, or Entresto (Sacubitril/Valsartan), is more likely to cause a maculopapular malar rash?

Entresto (Sacubitril/Valsartan) is Most Likely to Cause Maculopapular Malar Rash

Among the four medications listed, Entresto (sacubitril/valsartan) carries the highest risk for causing a maculopapular rash, as the valsartan component is a documented cause of exanthematous drug eruptions. 1

Evidence-Based Rationale

Entresto (Sacubitril/Valsartan) - Highest Risk

• Valsartan, a component of Entresto, has been directly implicated in causing diffuse erythematous maculopapular eruptions that typically appear within 3-10 days of therapy initiation and spread from the face throughout the entire body 1
• Histopathologic findings in valsartan-induced eruptions show lymphocyte exocytosis, spongiosis, necrotic keratinocytes, and perivascular eosinophilic infiltrates—classic features of drug-induced exanthematous reactions 1
• ACE inhibitors and angiotensin receptor blockers (ARBs) are recognized causes of drug hypersensitivity syndrome (DRESS), which presents with maculopapular rash, fever, lymphadenopathy, and organ involvement 2
• The valsartan component specifically has been documented to cause exanthematous drug reactions, with physicians advised to consider ARBs as triggering factors 1

Eplerenone - Moderate Risk

• Beta-blockers (eplerenone is a mineralocorticoid receptor antagonist, structurally related) are listed among drugs associated with drug hypersensitivity syndrome presenting with maculopapular rash 2
• However, direct case reports of eplerenone causing maculopapular rash are less documented than valsartan

Apixaban - Low Risk

• The FDA label for apixaban mentions "skin rash" as a possible allergic reaction but does not specifically describe maculopapular morphology 3
• Apixaban's cutaneous reactions are more commonly described as generalized allergic rash rather than the specific maculopapular pattern 3

Dapagliflozin - Lowest Risk

• SGLT2 inhibitors like dapagliflozin are not prominently featured in literature regarding maculopapular rashes
• Their most common dermatologic adverse effects involve genital mycotic infections rather than drug eruptions

Clinical Context and Mechanism

Maculopapular drug eruptions are the most frequently reported cutaneous adverse drug reaction pattern, affecting 1-3% of multimedicated patients 4. The reaction typically represents a delayed-type hypersensitivity response occurring days to weeks after drug initiation 1.

Key Distinguishing Features:

• The interval between drug initiation and rash onset for ARBs/ACE inhibitors may be at least one month, potentially leading to underdiagnosis 2
• The rash is usually pruritic, erythematous, and maculopapular, beginning on the face and spreading centrifugally 1
• Unlike urticarial reactions (which occur in about one-third of drug reactions), maculopapular eruptions represent about two-thirds of cutaneous drug reactions 4

Important Clinical Caveat

If a patient on Entresto develops a maculopapular rash with systemic symptoms (fever, lymphadenopathy, eosinophilia, organ involvement), consider DRESS syndrome, which requires immediate drug discontinuation 2. ACE inhibitors and ARBs are recognized triggers for this potentially severe reaction 2.

The diagnosis relies on temporal relationship (drug started within weeks to months before rash), characteristic morphology (maculopapular pattern), and resolution upon drug withdrawal 1, 4.