What are the black box warnings for Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs)?

Black Box Warnings for ACE Inhibitors and ARBs

The primary black box warning for both ACE inhibitors and ARBs is pregnancy-related: these medications cause fetal toxicity and death when used during the second and third trimesters, and must be discontinued immediately upon pregnancy detection. 1

Pregnancy Contraindication (The Only True Black Box Warning)

• Avoid ACE inhibitors and ARBs in pregnancy - they cause oligohydramnios, fetal renal dysfunction, skull hypoplasia, and neonatal death when used during the second and third trimesters 1
• Discontinue these medications as soon as pregnancy is detected 1
• This is the formal FDA black box warning that appears in the prescribing information for all drugs in these classes 1

Critical Safety Warnings (Not Formal Black Box Warnings, But Equally Important)

Angioedema Risk

• Do not use ACE inhibitors in patients with a history of angioedema with ACE inhibitors 1
• For patients with ACE inhibitor-associated angioedema, ARBs can be initiated only after waiting 6 weeks following ACE inhibitor discontinuation 1
• Do not use ARBs in patients with a history of angioedema with ARBs 1

Dual RAAS Blockade is Contraindicated

• Never combine ACE inhibitors with ARBs - this combination is explicitly contraindicated and potentially harmful 1, 2
• The combination increases risk of hyperkalemia and acute kidney injury without providing additional cardiovascular or renal benefits 2, 3
• Never combine ACE inhibitors, ARBs, and/or direct renin inhibitors - simultaneous use of any two or more of these agents is contraindicated 1
• The European Society of Cardiology and American College of Cardiology guidelines both state that dual RAAS blockade is not recommended 1, 2

Bilateral Renal Artery Stenosis

• Absolute contraindication in bilateral renal artery stenosis - ACE inhibitors and ARBs can precipitate acute kidney injury by preventing compensatory efferent arteriolar vasoconstriction 1, 3
• Also contraindicated in severe unilateral renal artery stenosis in a solitary kidney 1

Hyperkalemia Risk

• Increased risk of hyperkalemia, especially in patients with CKD or those on potassium supplements or potassium-sparing drugs 1
• Monitor serum potassium within 1 month of initiation, after dose adjustments, and periodically during therapy 3
• The risk is substantially elevated when combining with aldosterone antagonists (spironolactone, eplerenone) - use this combination with extreme caution and close monitoring 2

Monitoring Requirements to Prevent Serious Adverse Events

• Check serum creatinine within 1-2 weeks of initiation and after dose changes 3
• Accept creatinine increases up to 30% as physiologic and continue therapy 3
• Monitor serum potassium within 1 month of starting therapy and periodically thereafter 3
• Do not discontinue ACE inhibitors or ARBs based solely on eGFR decline unless creatinine rises more than 30% 3

Common Pitfalls to Avoid

• Do not combine ACE inhibitors with ARBs thinking it will provide better RAAS blockade - instead, optimize the dose of a single agent 2, 3
• Do not avoid these medications in advanced CKD (eGFR <30 mL/min/1.73 m²) - they remain beneficial but require closer monitoring and consider nephrology referral 3
• Do not immediately discontinue therapy if creatinine rises - an initial increase up to 30% is acceptable and typically returns to baseline 3
• Do not prescribe to women of childbearing potential without counseling about pregnancy risks and ensuring effective contraception 1