Lack of interaction between meloxicam and warfarin in healthy volunteers

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. In this study, we evaluated the risk factors for international normalized ratio (INR) increase, which is a surrogate marker of bleeding, after addition of an NSAID in a total of 98 patients who used warfarin. Patient age, sex, body mass index, maintenance warfarin dose, baseline INR, coadministered medications, underlying diseases, and liver and kidney functions were evaluated for possible risk factors with INR increase ≥15.0% as the primary end-point. Of the 98 patients, 39 (39.8%) showed an INR elevation of ≥15.0% after adding a NSAID to warfarin therapy. Multivariate analysis showed that high maintenance dose (>40 mg/week) of warfarin (P=0.001), the presence of coadministered medications (P=0.024), the use of meloxicam (P=0.025) and low baseline INR value (P=0.03) were the risk factors for INR increase in respect to NSAID-warfarin interaction. In conclusion, special caution is required when an NSAID is administered to warfarin users if patients are taking warfarin >40 mg/week and other medications interacting with warfarin.

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“…Turck et al, however, reported that meloxicam lacked interaction with warfain (17). Such divergent results can be explained as follows.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

et al. 2010

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“…It is also perhaps of interest that two other drugs highly bound to plasma proteinmeloxicam and losartan-do not significantly affect the pharmacokinetics and pharmacodynamics of warfarin. 24,25 Previous studies and clinical experience have shown that nateglinide is well tolerated in healthy volunteers and patients with type 2 diabetes. 8,22,23 In such studies performed in humans, nateglinide rapidly raises plasma insulin, with a corresponding reduction in plasma glucose in both healthy volunteers and patients with type 2 diabetes.…”

Section: Interaction Between Warfarin and Nateglinidementioning

confidence: 98%

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

Anderson¹,

Shelley²,

Crick³

et al. 2002

The Journal of Clinical Pharma

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The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two-group, two-way crossover, open-label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7- to 14-day washout, received both warfarin and nateglinide (120 mgnateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R- and S-enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.

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“…Warfarin is a well‐recognized narrow therapeutic index (NTI) drug with risks of bleeding complications (overdosing) and thrombosis (underdosing) often necessitating dedicated clinical pharmacology studies to evaluate drug–drug interactions (DDIs) for warfarin as the victim drug . To reduce the risk of causing bleeding in trial participants, warfarin DDI studies are typically conducted in healthy volunteers administered either single doses of warfarin or multiple doses titrated individually to achieve stable subtherapeutic anticoagulation levels ranging from 1.2‐ to 1.7‐fold of baseline as measured by the international normalization ratio (INR) of prothrombin time (PT) . In actual clinical practice, higher levels of INR are targeted for different indications, for example, an INR of 2.5 (range, 2–3) for patients with venous thromboembolism and atrial fibrillation or an INR of 3.0 (range, 2.5–3.5) for patients with certain mechanical heart valves .…”

mentioning

confidence: 99%

“…1,2 To reduce the risk of causing bleeding in trial participants, warfarin DDI studies are typically conducted in healthy volunteers administered either single doses of warfarin [3][4][5][6][7][8] or multiple doses titrated individually to achieve stable subtherapeutic anticoagulation levels ranging from 1.2-to 1.7-fold of baseline as measured by the international normalization ratio (INR) of prothrombin time (PT). [9][10][11][12] In actual clinical practice, higher levels of INR are targeted for different indications, for example, an INR of 2.5 (range, 2-3) for patients with venous thromboembolism and atrial fibrillation or an INR of 3.0 (range, 2.5-3.5) for patients with certain mechanical heart valves. 13 Historically, for a number of drugs, these dedicated warfarin DDI studies produced results that underpredicted the magnitude of observed drug interaction on warfarin in real-life patients, suggesting the need to improve the accuracy of prediction for warfarin drug interaction.…”

mentioning

confidence: 99%

Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor

Shi

Chen

Punwani

et al. 2016

The Journal of Clinical Pharma

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Drug-drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model-based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first-in-class indoleamine 2,3-dioxygenase 1 inhibitor in clinical development as a novel orally active immuno-oncological therapy. Observed data from a dedicated clinical DDI study using subtherapeutic warfarin suggested warfarin pharmacokinetics (PK), but not PD (anticoagulation), was significantly affected by concomitant epacadostat. However, subsequent PK/PD modeling and simulations indicated a clinically important DDI effect on warfarin PD at a higher baseline of the international normalization ratio (INR) and enabled recommendation of warfarin dose adjustment that is dependent on epacadostat dosing regimen and target INR.

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Lack of interaction between meloxicam and warfarin in healthy volunteers

Cited by 22 publications

References 25 publications

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor

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