What are the potential drug interactions with omeprazole (Proton Pump Inhibitor)?

Omeprazole Drug Interactions

Critical High-Risk Interactions

Omeprazole should be avoided with clopidogrel, as it reduces the antiplatelet drug's active metabolite by 46% and decreases platelet inhibition even when dosed 12 hours apart, potentially increasing cardiovascular event risk. 1

Antiplatelet Agents (Highest Clinical Priority)

• Clopidogrel: Omeprazole 80 mg reduces clopidogrel's active metabolite exposure by 46% on Day 1 and 42% on Day 5, with reduced platelet inhibition persisting regardless of dosing separation 1
• Alternative antiplatelet agents such as prasugrel or ticagrelor are less affected by PPI interactions and should be considered when antiplatelet therapy is required with acid suppression 2
• If a PPI is absolutely necessary with clopidogrel, pantoprazole is preferred over omeprazole due to lower CYP2C19 inhibition 2
• The American College of Cardiology explicitly recommends avoiding clopidogrel in patients taking CYP2C19 inhibitors including omeprazole 3

Anticoagulants

• Warfarin: Omeprazole inhibits CYP2C19, which can increase INR and prothrombin time, leading to abnormal bleeding or death 1
• Monitor INR and prothrombin time closely when initiating or discontinuing omeprazole in warfarin-treated patients 1
• The interaction is clinically significant primarily in extensive CYP2C19 metabolizers 4

Antiretroviral Medications (Contraindicated or Avoid)

• Rilpivirine: Concomitant use is contraindicated—omeprazole 20 mg daily decreases rilpivirine AUC by 40%, Cmax by 40%, and Cmin by 33%, risking treatment failure and resistance 1
• Atazanavir: Avoid concomitant use—omeprazole 40 mg daily decreases atazanavir AUC by 94%, Cmax by 96%, and Cmin by 95% 1
• Nelfinavir: Avoid concomitant use—omeprazole 40 mg daily decreases nelfinavir AUC by 36% and its active metabolite M8 by 92% 1
• Saquinavir: Omeprazole 40 mg daily increases saquinavir AUC by 82%, Cmax by 75%, and Cmin by 106%, requiring clinical and laboratory monitoring for toxicity 1

Moderate-Risk Interactions Requiring Monitoring

Methotrexate

• Omeprazole can elevate and prolong methotrexate and hydroxymethotrexate serum concentrations, particularly at high methotrexate doses, potentially causing toxicity 1
• Consider temporary withdrawal of omeprazole in patients receiving high-dose methotrexate 1

Other CYP2C19 Substrates

• Citalopram: Increased exposure leading to QT prolongation risk 1
• Cilostazol: Omeprazole 40 mg daily increases cilostazol Cmax by 18% and AUC by 26%, with greater increases (29% and 69%) in the active metabolite 3,4-dihydro-cilostazol 1
• Diazepam: Omeprazole decreases diazepam clearance and increases its half-life through CYP2C19 inhibition 5, 6
• Phenytoin: Omeprazole inhibits phenytoin metabolism, requiring monitoring of phenytoin levels 5, 7

Immunosuppressants

• Mycophenolate mofetil (MMF): Omeprazole 20 mg twice daily reduces MPA (active metabolite) Cmax by 52% and AUC by 23%, potentially reducing immunosuppressive efficacy 1
• Tacrolimus: Omeprazole can affect tacrolimus pharmacokinetics, requiring therapeutic drug monitoring 5

Antifungals and Other pH-Dependent Drugs

• Itraconazole and posaconazole: Reduced absorption due to increased gastric pH from omeprazole, potentially causing treatment failure 5
• Digoxin: Altered absorption possible due to pH changes, though clinical significance is debated 8
• Oral iron supplementation: Reduced absorption due to elevated gastric pH 5

Drugs That Reduce Omeprazole Efficacy

• St. John's Wort: Induces CYP2C9, 2C19, and 3A4, significantly increasing omeprazole clearance and reducing efficacy 4, 5
• Efavirenz: Induces omeprazole elimination, reducing its acid-suppressive effect 5
• Ginkgo biloba and yin zhi huang: May induce omeprazole metabolism 5

Drugs with Minimal or No Interaction

• Bupropion: No clinically significant interaction—bupropion is metabolized by CYP2B6, not CYP2C19, and can be co-administered without dose adjustment 9
• Clarithromycin: Increases omeprazole exposure (doubling AUC), but this is unlikely to have safety implications 8
• Ginseng, ginkgo, and ginger: Do not significantly affect omeprazole or interact with it at modest doses 4

Clinical Management Algorithm

Step 1: Identify High-Risk Combinations

• If patient is on clopidogrel: Switch to pantoprazole or consider H2-receptor antagonist (famotidine), or switch antiplatelet to prasugrel/ticagrelor 2
• If patient is on rilpivirine, atazanavir, or nelfinavir: Do not prescribe omeprazole—use alternative acid suppression 1
• If patient is on warfarin: Monitor INR closely when starting or stopping omeprazole 1

Step 2: Assess Moderate-Risk Medications

• For methotrexate (high-dose): Consider temporary omeprazole withdrawal or use alternative PPI 1
• For mycophenolate mofetil: Consider switching to enteric-coated mycophenolate sodium or using alternative PPI 5
• For phenytoin or diazepam: Monitor drug levels and adjust doses as needed 5

Step 3: Consider Gastric pH-Dependent Drugs

• For itraconazole, posaconazole, or iron: Separate administration or use alternative acid suppression 5

Step 4: Check for CYP450 Inducers

• If patient takes St. John's Wort or efavirenz: Omeprazole may be ineffective; consider alternative PPI or higher doses 5

Common Pitfalls to Avoid

• Do not assume all PPIs have identical interaction profiles—omeprazole and esomeprazole have stronger CYP2C19 inhibition than pantoprazole 2
• Do not separate omeprazole and clopidogrel dosing by 12 hours thinking this prevents interaction—it does not 1
• Do not confuse the omeprazole-clopidogrel interaction with the omeprazole-bupropion combination, which is safe 9
• Do not overlook genetic polymorphisms in CYP2C19, which can amplify or diminish interaction severity 4, 5
• Do not discontinue antiplatelet therapy due to interaction concerns without considering alternative strategies first 3