Interaction Between Low-Dose Methotrexate and Nonsteroidal Anti-inflammatory Drugs, Penicillins, and Proton Pump Inhibitors

Abstract

Given the available evidence, the clinical importance of the interaction between LD-MTX and NSAIDs, penicillins, and PPIs cannot be substantiated. Health care providers should assess the benefit and risk of LD-MTX regardless of concomitant drug use, including factors known to predispose patients to MTX toxicity, and continue to monitor clinical and laboratory parameters per guideline recommendations.

Concomitant use of low‐dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis

“…17 Results on pharmacokinetic parameters are conflicting. While concomitant use of NSAIDs did not significantly alter the pharmacokinetic profile of low-dose methotrexate in most studies, 14,17 individual studies have reported important pharmacokinetic changes, including decreased renal clearance of methotrexate with use of ibuprofen and etoricoxib. [28][29][30] Although inconsistent, these data may provide potential mechanistic support for the associations observed in this study.…”

“…There are no previous controlled studies of concomitant use of methotrexate and NSAIDs that have investigated adverse effects measured as hard clinical endpoints. Previous studies have been small scale and aimed primarily at assessing the pharmacokinetics of methotrexate . A small number of studies have also reported clinical toxicities or adverse effects; however, limitations in sample size and lack of proper control groups render these data largely inconclusive with respect to clinical outcomes .…”

“…Previous studies have been small scale and aimed primarily at assessing the pharmacokinetics of methotrexate. 14,17,18 A small number of studies have also reported clinical toxicities or adverse effects; however, limitations in sample size and lack of proper control groups render these data largely inconclusive with respect to clinical outcomes. 17 Results on pharmacokinetic parameters are conflicting.…”

“…Agents within drug class have been shown to inhibit the elimination of methotrexate, thereby leading to higher systemic concentrations that may, consequently, exacerbate the toxicity of methotrexate . Clinically significant drug‐drug interaction between high‐dose methotrexate, used in oncological conditions, and NSAIDs is a well‐recognized potential cause of serious methotrexate toxicity . While high‐ and low‐dose methotrexate differs with respect to potential for interaction, case reports and pharmacokinetic studies, although conflicting, have also suggested the possibility of clinically significant interaction with concomitant use of low‐dose methotrexate and NSAIDs.…”

“…Clinically significant drug‐drug interaction between high‐dose methotrexate, used in oncological conditions, and NSAIDs is a well‐recognized potential cause of serious methotrexate toxicity . While high‐ and low‐dose methotrexate differs with respect to potential for interaction, case reports and pharmacokinetic studies, although conflicting, have also suggested the possibility of clinically significant interaction with concomitant use of low‐dose methotrexate and NSAIDs. Although current product labels recommend caution when NSAIDs are administered with low‐dose methotrexate, there is a paucity of adequately powered controlled studies and studies that investigate hard end points; hence, evidence of the clinical impact of this drug combination on adverse outcomes is lacking.…”