Warnings for ACE inhibitor side effects strengthened by MHRA

Healthcare professionals should be aware of the potential for delayed onset of adverse events relating to ACE inhibitors, even after weeks or years of use, the Medicines and Healthcare products Regulatory Agency (MHRA) has warned.

The MHRA has strengthened warnings relating specifically to the risk of delayed-onset of angioedema – a rare side-effect of ACE inhibitor treatment – and highlighted the importance of distinguishing between allergic and non-allergic reactions.

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Angioedema is characterised by localised swelling of subcutaneous or submucosal tissues. Symptoms may involve the swelling of the tongue, lips, and upper airway, and can be life-threatening.

Unlike histamine-mediated (allergic) angioedema, bradykinin-mediated (non-allergic) angioedema usually occurs without the formation of hives or a rash and typically has a slower onset. Both, however, can have a delayed onset from ACE inhibitors, happening after weeks or even years of use.

The medicines’ watchdog emphasised that distinction between histamine-mediated (allergic) angioedema and bradykinin-mediated (non-allergic) angioedema is crucial as treatment strategies differ significantly.

Importantly, bradykinin-mediated angioedema is unlikely to respond to standard anaphylaxis treatments including adrenaline.

Therefore, lack of response to standard anaphylaxis treatments should prompt consideration of bradykinin-mediated angioedema, with treatment informed by clinical protocols.

If angioedema is suspected in a patient taking an ACE inhibitor, discontinue the ACE inhibitor immediately and do not restart.

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The product information for all ACE inhibitors is being updated to strengthen the warnings on the risk of delayed-onset angioedema, which may still occur after weeks to years of use.

This update is the result of a review of UK Yellow Card data up to and including 10 June 2026, which revealed that approximately one-half of angioedema cases with reported time-to-onset occurred 30 days or more after initiation of treatment with ACE inhibitors.

Manufacturer data subsequently indicated that around 20–30% of reported cases occurred after at least 30 days of therapy. The MHRA note that this pattern of delayed onset is more associated with bradykinin-mediated angioedema.

ACE inhibitors are indicated for the treatment of hypertension, heart failure, post-myocardial infarction management, diabetic nephropathy, and cardiovascular risk reduction.

Certain populations, including older adults, women, people who smoke and patients of Black or African Caribbean ethnicity, may be at increased risk of angioedema.

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