From the Guidelines
Proton pump inhibitors (PPIs) interact with several medications, including clopidogrel, warfarin, diazepam, and phenytoin, due to their effects on gastric pH and metabolism, and patients should be aware of these potential interactions to avoid harmful drug interactions. The interactions between PPIs and other medications can lead to reduced absorption of certain medications, increased blood levels of other medications, or reduced effectiveness of medications like clopidogrel. Some of the key interactions include:
- Reduced absorption of medications requiring acidic environments like ketoconazole, itraconazole, and iron supplements
- Increased blood levels of diazepam, warfarin, and phenytoin by competing for liver enzyme metabolism
- Reduced effectiveness of clopidogrel by inhibiting its conversion to its active form
- Increased digoxin levels and methotrexate toxicity
- Reduced absorption of certain HIV medications like atazanavir
- Altered blood levels of tacrolimus and mycophenolate mofetil, requiring monitoring in transplant patients These interactions occur because PPIs alter stomach acidity, affecting drug dissolution and absorption, and because they compete for cytochrome P450 enzymes in the liver, particularly CYP2C19, as noted in studies such as 1. It is essential for patients to inform their healthcare providers about all medications they are taking, including over-the-counter PPIs like omeprazole, to avoid potentially harmful drug interactions, and to consider alternative medications or monitoring strategies as needed, as suggested by studies like 1 and 1. In particular, the use of PPIs with clopidogrel has been associated with adverse cardiovascular outcomes in some studies, although the evidence is not consistent, and the FDA has advised healthcare providers to reevaluate the need for starting or continuing treatment with a PPI in patients taking clopidogrel, as noted in 1. Overall, patients and healthcare providers should be aware of the potential interactions between PPIs and other medications, and take steps to minimize the risks of harmful drug interactions.
From the FDA Drug Label
Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole Sodium and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with pantoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with pantoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12. 3)].
Table 3: Clinically Relevant Interactions Affecting Drugs Coadministered with Dexlansoprazole and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with dexlansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with dexlansoprazole may increase toxicity of the antiretroviral drugs.
PPI Interactions:
- Antiretrovirals:
- Rilpivirine: Concomitant use with PPIs is contraindicated.
- Atazanavir and nelfinavir: Avoid concomitant use with PPIs.
- Saquinavir: Monitor for potential saquinavir toxicities.
- Warfarin: Monitor INR and prothrombin time, and adjust warfarin dose as needed.
- Methotrexate: Consider temporary withdrawal of PPI in patients receiving high-dose methotrexate.
- Digoxin: Monitor digoxin concentrations, and adjust dose as needed.
- Drugs dependent on gastric pH for absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole): PPIs can reduce absorption of these drugs due to decreased intragastric acidity.
- Clopidogrel: Concomitant use with omeprazole may reduce plasma concentrations of the active metabolite of clopidogrel and reduce platelet inhibition. 2, 3, 4
From the Research
Drug Interactions with PPIs
- PPIs can interact with various drugs, including:
- Clopidogrel: The use of PPIs with clopidogrel may decrease the antiplatelet activity of clopidogrel, although the effect may vary depending on the specific PPI used 5
- Warfarin: PPIs may reduce the risk of warfarin-related gastrointestinal bleeding, but may also affect warfarin control as measured by time in therapeutic range (TTR) 6, 7
- Antiplatelet drugs: The combination of PPIs with antiplatelet drugs may increase the risk of major adverse cardiovascular events (MACEs) 8
- Nonsteroidal anti-inflammatory drugs (NSAIDs): PPIs may reduce the risk of upper gastrointestinal bleeding in patients taking warfarin with NSAIDs 9
Specific PPI Interactions
- Omeprazole: May decrease the antiplatelet effects of clopidogrel 5
- Pantoprazole: May have no significant effect on the antiplatelet response to clopidogrel 5
- Lansoprazole: May have no significant effect on the antiplatelet response to clopidogrel 5
- Esomeprazole: May have no significant effect on the antiplatelet response to clopidogrel 5
- Rabeprazole: May not increase the risk of MACEs when used with clopidogrel 8