What are the absolute and relative contraindications to initiating a proton‑pump inhibitor (PPI)?

Contraindications for Initiation of PPI

The only absolute contraindication to initiating a PPI is known hypersensitivity to the specific PPI formulation or any substituted benzimidazole, and concurrent use of rilpivirine-containing products. 1

Absolute Contraindications

Hypersensitivity Reactions

• Known hypersensitivity to the specific PPI or any substituted benzimidazole is an absolute contraindication. 1
• Hypersensitivity reactions can manifest as anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria. 1, 2
• Anaphylaxis is the most common clinical presentation in patients with immediate hypersensitivity reactions to PPIs, followed by urticaria and/or angioedema. 2

Drug Interactions

• Concurrent use of rilpivirine-containing products is an absolute contraindication to all PPIs. 1
• This represents a class effect due to acid suppression reducing rilpivirine absorption and efficacy. 1

Important Clinical Considerations: No Relative Contraindications Exist

There are no relative contraindications to PPI initiation when a valid indication exists. The 2022 American Gastroenterological Association guidelines emphasize that PPIs are generally safe, and concerns about potential adverse events should not prevent initiation when clinically indicated. 3

Situations That Are NOT Contraindications

Renal Impairment

• Renal impairment is not a contraindication to PPI initiation. 4
• There is minimal risk from PPI administration even to patients with significant renal impairment because there is no direct toxicity from PPIs. 4

Hepatic Impairment

• Hepatic impairment is not a contraindication to PPI initiation. 4
• Despite significant hepatic metabolism of all PPIs, there is minimal risk in patients with significant hepatic impairment due to the absence of direct PPI toxicity. 4

Advanced Age

• Advanced age alone is not a contraindication. 5
• In fact, age >60 years is a risk factor for upper GI bleeding that may strengthen the indication for PPI therapy, particularly in patients on anticoagulants or NSAIDs. 5

Concerns About Long-Term Adverse Effects

• Theoretical concerns about long-term adverse effects (osteoporosis, dementia, infections, cardiovascular risk) are not contraindications to PPI initiation when a valid indication exists. 6, 7
• All studies reporting associations between PPIs and serious adverse events have been observational and cannot establish causality, while randomized controlled trials comparing PPIs with placebo have consistently shown no higher rate of adverse events among PPI users. 6, 7

Critical Clinical Pitfalls to Avoid

Cross-Reactivity Among PPIs

• A history of hypersensitivity to one PPI does not automatically contraindicate all PPIs. 2, 8
• Cross-reactivity exists among PPIs but is not universal. 2, 9
• Skin testing can identify safe alternative PPIs, and tolerance to PPIs with negative skin tests should be established with a negative oral challenge test. 8
• When an alternative PPI cannot be found, H2-receptor antagonists can be prescribed or a PPI desensitization protocol can be applied. 8

Distinguishing True Contraindications from Inappropriate Use

• The absence of a valid indication is not the same as a contraindication. 3
• All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing, but this reflects inappropriate prescribing rather than a contraindication to initiation. 3

Genetic Polymorphisms

• CYP2C19 genetic polymorphisms are not contraindications to PPI initiation. 4
• While genetic polymorphisms substantially increase plasma levels of omeprazole, lansoprazole, and pantoprazole (but not rabeprazole), this does not contraindicate their use but may influence drug selection. 4

Practical Algorithm for PPI Initiation

1. Screen for absolute contraindications:

   • Known hypersensitivity to the specific PPI or substituted benzimidazoles 1
   • Concurrent rilpivirine-containing products 1

2. If absolute contraindications are absent, proceed with PPI initiation when a valid indication exists. 3

3. If history of hypersensitivity to one PPI exists:

   • Consider alternative PPI with allergist consultation and skin testing 8
   • Consider H2-receptor antagonist as alternative 8
   • Consider desensitization protocol if no alternative available 8

4. Document the specific indication for PPI use clearly in the medical record. 3