5 Pantoprazole Interactions to be Aware for Safe Use

Introduction: Pantoprazole Interactions to be Aware for Safe Use

When you suffer from too much acid in your stomach or heartburn, pantoprazole may help. This proton-pump inhibitor (PPI) treats conditions when the stomach acid returns and can hurt the esophagus, a disease called gastroesophageal reflux or GERD. (1-3)

Thanks to the decreased acid in the stomach for a whole day, pantoprazole allows the esophagus to heal and prevents further damage. However, the lower acid in the stomach can negatively affect some medications. Medications that need acid pH for absorption will be less available in the body and consequently show lower therapeutic effects. Moreover, pantoprazole can cause intensive bleeding if used with the blood thinner warfarin. (2-3)

This article is about pantoprazole interactions with certain medications. Keep reading to learn about the cause of those interactions and when pantoprazole is contraindicated due to the high risk of side effects.

Pantoprazole Interactions

1. Antiretrovirals

Antiretrovirals are medications that reduce the amount of human immunodeficiency virus (HIV) in the body, which damages the immune system and are used to fight against HIV infection. If the infection is not treated, the infected individual will develop Acquired Immune Deficiency Syndrome (AIDS). (4)

Pantoprazole interacts with some antiretroviral medications and causes different implications. Pantoprazole may reduce the clinical effect of rilpivirine or nelfinavir when used together. Pantoprazole reduces acid pH that does not favor rilpivirine or nelfinavir absorption. This will lead to decreased exposure to such antiretroviral drugs and decreased antiviral effect. In the end, HIV may become resistant to the therapy. Therefore, regulatory bodies recommend avoiding pantoprazole usage in patients who use medications containing rilpivirine or nelfinavir. (2-3)

Pantoprazole can cause the opposite effect, increasing exposure to antiretroviral drugs, such as saquinavir. In this case, the concomitant use may cause saquinavir toxicity, an increased risk of side effects, or severity. (2, 3, 5)

Some of the common toxicity signs are:

  • Diarrhea,
  • Abdominal discomfort,
  • Headache,
  • Nausea, or
  • Skin rash.

Rarely, it can cause liver injury and exacerbation of an underlying chronic hepatitis B or C. (6-7)

Therefore, pantoprazole or other PPI should be used cautiously with saquinavir. The healthcare professional will monitor potential saquinavir toxicity through gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation. (8)

2. Warfarin

Warfarin is a blood thinner, a medication that protects the body from forming or growing bigger blood clots in the context of several diseases. (9) In patients on warfarin therapy, pantoprazole or other PPI increases the International normalized ratio (INR) and prothrombin time (PT). (2-3)

PT is the time the body needs to form clots, and INR is a test that doctors use to assess the risk of bleeding. (10)

Blood clots protect the body from bleeding at the place where there is an injury. If clots are formed in other body parts where the injury does not exist, they can be a threat and can cause stroke, heart attack, or deep vein thrombosis. Anticoagulants such as warfarin make forming blood clots harder in the heart, arteries, and veins. In addition, thanks to warfarin, the already-formed clots cannot get bigger and become a more severe threat. (11)

Warfarin is a mixture of S-warfarin and R-warfarin isomers, where S-warfarin is 3–5 times more potent. CYP2C9 enzyme from a P450 (CYP) family is responsible for the metabolism of S-warfarin. When taking pantoprazole, it inhibits CYP2C9 activity and cannot metabolize S-warfarin as it usually does. (12)

This interaction between pantoprazole and warfarin may lead to abnormal bleeding and even death. If you take both medications, your doctor will closely monitor INR and prothrombin time and adjust the warfarin dose accordingly. (2-3)

3. Clopidogrel

Clopidogrel is a medication that reduces the risk of myocardial infarction (MI) and stroke by preventing platelets from aggregating. (13) When pantoprazole is used in patients taking clopidogrel, the study showed that the active metabolite of clopidogrel was reduced by approximately 14%. (2-3)

Although pantoprazole inhibits CYP2C19, responsible for clopidogrel metabolism, due to the weakest effect among other medications in this class, the American Heart Association/American Stroke Association guidelines from 2014 allow its concomitant usage with clopidogrel. (13)

However, the clinical importance of this drug-drug interaction effect is still being determined. Results from a study showed that pantoprazole at high doses is not associated with any changes in the clopidogrel effects, despite the timing of the drug administration. (14)

Yet, until more clear clinical conclusions become available for healthcare professionals, the latest recommendation to prescribers for concomitant use of pantoprazole and clopidogrel is to evaluate on an individual base based on risk-benefit assessment. (13)

4. Methotrexate

In patients who take high doses of methotrexate, concomitant usage with PPI, including pantoprazole, may cause a toxic effect. (2-3)

Methotrexate slows the growth of cells. This effect has a positive therapeutic result in several types of cancer or psoriasis. Methotrexate is also used for the treatment of rheumatoid arthritis. (15)

Ten years ago, it was found in literature reports that pantoprazole affects the elimination of methotrexate from the body. Although the mechanism of this interference is unclear, the clinical evidence showed increased levels of methotrexate or its active metabolite hydroxy-methotrexate in patients who used PPI. (16)

Increased concentrations of methotrexate in plasma and longer duration for elimination may lead to toxicity, manifested with:

  • Bone marrow suppression,
  • Gastrointestinal ulcers,
  • Side effects on the skin,
  • Pulmonary toxicity,
  • Nephrotoxicity, and
  • Hepatotoxicity.

Methotrexate toxicity may require hospitalization and medical treatment in the intensive care unit. (17)

Because of this, the doctor may discontinue pantoprazole therapy in some patients that use high doses of methotrexate. (2-3)

5. Drugs Dependent on Gastric pH for Absorption

The clinical effect of drugs that need physiologic gastric pH for absorption is affected by pantoprazole and other acid-reducing agents.

As a result of the long-acting mechanism, pantoprazole can stop acid secretion in the stomach for 24 hours. (18) During this period, the stomach has less acid pH, which can impact the other drugs. In an increased gastric pH, the dissolution of the weakly acidic drugs is increased while decreased of the weakly basic drugs. Such effects on drugs’ dissolution would result in an altered absorption rate and/or extent. (19)

Medications that need an acid environment for absorption are:

  • Iron salts,
  • Mycophenolate mofetil,
  • Ketoconazole/itraconazole,
  • Nilotinib,
  • Erlotinib,
  • Dasatinib, etc. (2, 3, 18)

Your doctor needs to know the medications you take to asses if pantoprazole may impact its therapeutic effect.


Pantoprazole interactions include those with HIV drugs, methotrexate, warfarin, and medications that need acid pH for absorption. Therefore, pantoprazole is not recommended for use in patients using rilpivirine or nelfinavir.

In patients using warfarin, the doctor will monitor PT and INR due to the risk of intensive and life-threatening bleeding.

Pantoprazole is a PPI with fewer interactions compared to others from the group. However, as with any medication, tell your doctor the treatment you take so the doctor will know if there is a risk of possible interaction and side effects.

See Also

Metronidazole Interactions

Tramadol Contraindications

Tramadol Side Effects

Tramadol Interactions

Gabapentin Interactions

Shingles Vaccine Side Effects

Lisinopril Contraindications

Is Ibuprofen a Blood Thinner?

Do Blood Thinners Affect Oxygen Levels?

What is Creatinine Level in Blood Tests?

Acetaminophen Contraindications

Aspirin Contraindications

  1. MedlinePlus, Pantoprazole, 2022 Apr, https://medlineplus.gov/druginfo/meds/a601246.html
  2. Food and Drug Administration, PROTONIX (pantoprazole sodium) delayed-release tablets, for oral use, for delayed-release oral suspension, Prescribing Information, 2020 Nov, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020987s056,022020s018lbl.pdf
  3. Food and Drug Administration, PANTOPRAZOLE SODIUM for injection, for intravenous use, Prescribing Information, 2022 Mar, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209463s015lbl.pdf
  4. Centers for Disease Control and Prevention, HIV, 2022 Jul, https://www.cdc.gov/hiv/basics/livingwithhiv/treatment.html
  5. Drugbank online, Saquinavir, 2023 Apr, https://go.drugbank.com/drugs/DB01232
  6. Clinicalinfo.HIV.gov, Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, 2018 may https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/saquinavir#:~:text=Major%20Toxicities,of%20chronic%20liver%20disease%2C%20lipodystrophy.
  7. National Library of Medicine, Saquinavir, 2017 Sep, https://www.ncbi.nlm.nih.gov/books/NBK548019/
  8. Dailymed, INVIRASE, (saquinavir mesylate) tablets, film-coated, 2021 Jun, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c00d1607-ac36-457b-a34b-75ad74f9cf0a
  9. MedlinePlus, Warfarin, 2017 Jun https://medlineplus.gov/druginfo/meds/a682277.html#:~:text=Warfarin%20is%20used%20to%20prevent,have%20suffered%20a%20heart%20attack.
  10. National Library of Medicine, International Normalized Ratio (INR), 2022 May, https://www.ncbi.nlm.nih.gov/books/NBK507707/
  11. American Heart Association. What are Anticoagulants and Antiplatelet Agents? https://www.heart.org/-/media/files/health-topics/answers-by-heart/what-are-anticoagulants-and-antiplatelet-agents.pdf
  12. S. Chandelia and N. K. Dubey, Warfarin-induced raised international normalized ratio is further prolonged by pantoprazole, Indian J Crit Care Med. 2016 Feb; 20(2): 127–128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810929/
  13. University of Illinois Chicago, What is the clinical relevance of the clopidogrel/proton pump inhibitor (PPI) interaction?, 2019 Oct, https://dig.pharmacy.uic.edu/faqs/2019-2/october-2019-faqs/what-is-the-clinical-relevance-of-the-clopidogrel-proton-pump-inhibitor-ppi-interaction/
  14. J. L. Ferreiro, M. Ueno, S. D. Tomasello, et al., Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects, Circ Cardiovasc Interv. 4(3):273-9. https://pubmed.ncbi.nlm.nih.gov/21521834/
  15. MedlinePlus, Methotrexate, 2017 Apr, https://medlineplus.gov/druginfo/meds/a682019.html#:~:text=Methotrexate%20is%20in%20a%20class,activity%20of%20the%20immune%20system.
  16. S. Bezabeh, A. C. Mackey, P. Kluetz, D. Jappar, and J. Korvickb, Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors, Oncologist. 2012 Apr; 17(4): 550–554. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336837/
  17. K.M. Hamed, I. M. Dighriri, A. F. Baomar, et al., Overview of Methotrexate Toxicity: A Comprehensive Literature Review, Cureus. 2022 Sep; 14(9): e29518. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9595261/#:~:text=MTX%20toxicity%20may%20appear%20as,dermatological%20side%20effects%20%5B69%5D.
  18. National Library of Medicine, Pantoprazole, 2022 Jul, https://www.ncbi.nlm.nih.gov/books/NBK499945/
  19. D. Patel, R. Bertz, S. Ren, D. W. Boulton and M. Någård, A Systematic Review of Gastric Acid-Reducing Agent-Mediated Drug–Drug Interactions with Orally Administered Medications, Clinical Pharmacokinetics volume 59, pages 447–462 (2020) https://link.springer.com/article/10.1007/s40262-019-00844-3


Follow us