Gemfibrozil and Loperamide: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Loperamide
Gemfibrozil
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
An increased loperamide exposure and an increased risk of loperamide-related adverse reactions
Interaction Deep Dive
Coadministration of loperamide and gemfibrozil (CYP2C8 inhibitor) may increase the exposure of loperamide and may increase a risk for cardiac adverse reactions, especially in patients who are taking multiple CYP enzyme inhibitors (eg, when combined with itraconazole a CYP3A4 inhibitor). Monitor patients for cardiac adverse reactions1. In vitro studies have reported that loperamide is primarily metabolized by the cytochrome P450 (CYP) 2C8 and 3A4 enzymes to its main in vivo metabolite, N-desmethyl-loperamide. Loperamide is also a substrate of the P-glycoprotein efflux transporter. In contrast, gemfibrozil is a potent inhibitor of CYP2C8. In one in vivo study (n=12), coadministration of loperamide and gemfibrozil resulted in significant increases in loperamide Cmax (1.6-fold), AUC(0 to infinity) (2.2-fold), and the elimination half-life (11.9 to 16.7 hours; p less than 0.05 for all measures) 2.
Why it happens (mechanism)
Inhibition of CYP2C8-mediated metabolism of loperamide
Literature reports
3 reports — tap to read
a) In drug interaction studies, When a single 4 mg dose of loperamide hydrochloride was coadministered with 600 mg gemfibrozil, a strong inhibitor of CYP2C8, on day 3 of a 5-day treatment with gemfibrozil twice daily, the mean peak plasma concentration and the systemic exposure to loperamide was increased by 1.6-fold and 2.2-fold, respectively 1.
b) When multiple doses of both 100 mg itraconazole and 600 mg gemfibrozil (CYP2C8 inhibitor) twice daily were administered with a single 4 mg dose of loperamide hydrochloride, the mean peak plasma concentration and the systemic exposure to loperamide was increased by 4.2-fold and 12.6-fold, respectively 1.
c) In a randomized, 4 phase, crossover study of 12 healthy volunteers, itraconazole, gemfibrozil and their combination markedly increased the plasma concentrations of loperamide. Patients were randomly assigned to itraconazole (200 mg first dose and then 100 mg), gemfibrozil (600 mg), both itraconazole and gemfibrozil, or placebo, orally twice daily for 5 days. On day 3, all patients received a single 4-mg dose of loperamide. Plasma and urine loperamide and N-desmethyl-loperamide concentrations were obtained for up to 72 hours and 48 hours, respectively. Itraconazole increased loperamide Cmax 2.9-fold (range, 1.2 to 5; p less than 0.001), AUC(0 to infinity) 3.8-fold (1.4 to 6.6; p less than 0.001), and prolonged the elimination half-life of loperamide from 11.9 to 18.7 hours (p less than 0.001). Gemfibrozil increased loperamide Cmax 1.6-fold (0.9 to 3.2; p less than 0.05), AUC(0 to infinity) 2.2-fold (1 to 3.7; p less than 0.05), and prolonged the elimination half-life of loperamide to 16.7 hours (p less than 0.01). The amount of loperamide excreted into urine within 48 hours was increased by itraconazole (3-fold; p less than 0.001), gemfibrozil (1.4-fold; p less than 0.05) and their combination (5.3-fold; p less than 0.001). The renal clearance of loperamide was decreased by gemfibrozil and the combination of gemfibrozil and itraconazole by 28% (p less than 0.05) and 34% (p less than 0.01), respectively. The plasma AUC(0 to 72) ratio of N-desmethyl-loperamide to loperamide was reduced by itraconazole, gemfibrozil and their combination by 65%, 46% and 88%, respectively (p less than 0.001). No significant differences were observed in the Digit Symbol Substitution Test or subjective drowsiness between the phases 2.
Common questions
Can I take Gemfibrozil and Loperamide together?
An increased loperamide exposure and an increased risk of loperamide-related adverse reactions Always confirm with your pharmacist or prescriber before making any change.
How serious is the Gemfibrozil and Loperamide interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Gemfibrozil or Loperamide need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
- Product Information: Loperamide hydrochloride oral capsules, loperamide hydrochloride oral capsules. Mylan Pharmaceuticals Inc (per DailyMed), Morgantown, WV, 2022. DailyMed
- Niemi M, Tornio A, Pasanen MK, et al: Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol 2006; 62(6):463-472. PubMed
Keep reading about Loperamide
Keep reading about Gemfibrozil
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