Can Losartan (angiotensin II receptor antagonist), Hydrochlorothiazide (HCTZ) (thiazide diuretic), and Metformin (biguanide antidiabetic) suddenly cause a rash?

Can Losartan, HCTZ, and Metformin Suddenly Cause Rash?

Yes, all three medications—losartan, hydrochlorothiazide (HCTZ), and metformin—can cause rash, though the likelihood and mechanisms differ significantly among them.

Losartan and Rash

Losartan can cause cutaneous reactions including rash, though this is relatively uncommon. 1

• The FDA label for losartan reports erythroderma (widespread rash) as a postmarketing adverse reaction 1
• Angioedema, including swelling of the face, lips, pharynx, and tongue, has been reported rarely with losartan, and some patients who experienced this had previously experienced angioedema with ACE inhibitors 1
• Case reports document anaphylaxis with urticarial rash occurring within an hour of losartan administration 2
• Hypersensitivity reactions including angioedema and rash have been documented in postmarketing surveillance 1, 3

Important caveat: While losartan was initially thought to avoid the cutaneous side effects seen with ACE inhibitors, postmarketing experience has shown that similar reactions can occur, though they remain rare 3, 2

Hydrochlorothiazide (HCTZ) and Rash

HCTZ is a well-established cause of photosensitive skin reactions and should be considered the most likely culprit among these three medications. 4

• Thiazide diuretics, including HCTZ, can trigger multiple types of photosensitive eruptions: exaggerated sunburn reactions, dermatitis, and lichenoid eruptions 4
• Drug-induced photosensitivity from HCTZ occurs when the drug is present in the skin and exposed to ultraviolet or visible radiation 4
• The reaction can develop suddenly even after prolonged stable use, particularly with increased sun exposure during travel or seasonal changes 4

Key clinical point: Patients taking HCTZ should be specifically counseled about sun protection, including seeking shade during midday, wearing protective clothing and broad-brimmed hats, and using broad-spectrum sunscreen with SPF 30 or higher 4

Metformin and Rash

Metformin can cause rash, though this is less common than with the other two medications. 5

• The FDA label reports rash as occurring in ≥1% to ≤5% of metformin-treated patients, more commonly than with placebo 5
• Rash led to discontinuation in some patients during clinical trials 5
• The mechanism is not well-characterized but appears to be a hypersensitivity reaction 5

Practical Diagnostic Approach

When evaluating a patient on this combination who develops rash, systematically assess:

1. Sun exposure history: Recent travel, outdoor activities, or seasonal changes strongly suggest HCTZ-induced photosensitivity 4

2. Timing of medication initiation or dose changes: Rash occurring within days to weeks of starting or increasing any of these medications suggests drug hypersensitivity 1, 2

3. Distribution pattern:

   • Sun-exposed areas (face, neck, arms, hands) → HCTZ photosensitivity 4
   • Generalized distribution → consider losartan or metformin 5, 1

4. Associated symptoms:

   • Facial swelling, lip swelling, or respiratory symptoms → losartan-induced angioedema requiring immediate intervention 1, 2
   • Pruritus alone → any of the three medications 6, 5, 1

Management Algorithm

For mild rash without systemic symptoms:

• Discontinue the most likely offending agent based on the assessment above 6
• For suspected HCTZ photosensitivity, strict sun avoidance and protective measures while continuing the medication may be attempted if blood pressure control is critical 4
• Topical therapies and systemic antihistamines can be used for symptomatic relief 6

For severe rash or any signs of angioedema:

• Immediately discontinue losartan and administer epinephrine if angioedema involves airway 1, 2
• Consider short courses of systemic steroids for severe cutaneous reactions 6
• Do not rechallenge with the suspected medication 2

Critical pitfall: Do not assume that because a patient has tolerated these medications for months or years that they cannot be the cause of a new rash—drug reactions can occur at any time during therapy, particularly with photosensitizing agents like HCTZ when environmental exposure changes 4, 3