Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy

STUDY OBJECTIVE: To evaluate the effect of levofloxacin coadministration on the international normalized ratio (INR) in patients receiving warfarin therapy. DESIGN: Prospective analysis. SETTING: Outpatient clinic at a Veterans Affairs medical center. PATIENTS: Eighteen adult patients receiving warfarin. INTERVENTION: On the basis of clinical diagnosis and judgment, levofloxacin was prescribed to the 18 patients for treatment of various types of infection. The INR was measured before and at 2-8-day intervals after the coadministration of levofloxacin therapy, and once after completing therapy. Warfarin dosages were adjusted when necessary. MEASUREMENTS AND MAIN RESULTS: Warfarin dosages were changed in seven patients as a result of the first nontherapeutic INR values obtained after start of levofloxacin therapy. Owing to a concern regarding noncompliance and the adverse effect of bleeding, warfarin dosage was adjusted in one patient even though his first INR value was in the high end of the therapeutic range (2.98, therapeutic range 2-3). One patient withdrew from the study after the first INR measurement after levofloxacin coadministration. Because of a concern about the possible bleeding complication, warfarin dosage was also adjusted in this patient after obtaining his first INR value. Therefore, only the INR values obtained before and the first INR values obtained after levofloxacin administration were compared to evaluate the effect of levofloxacin on INR determination of warfarin therapy. The INR values obtained before levofloxacin administration did not differ significantly from the first INR values obtained after levofloxacin coadministration (mean +/- SD 2.61 +/- 0.44 vs 2.74 +/- 0.83, 95% confidence interval -0.449-0.196, p=0.419). CONCLUSION: The INR values measured before and after concomitant levofloxacin therapy were not significantly different. However, the ability to detect a significant difference may be affected by the small number of patients studied. Further studies with a larger sample are required to better determine the effect of levofloxacin coadministration on INR monitoring during warfarin therapy     

Lack of interaction between meloxicam and warfarin in healthy volunteers

Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUC_SS values for the more potent S-enantiomer were 5.07 mg · h · l⁻¹ (27.5%) for warfarin alone and 5.64 mg · h · l⁻¹ (28.1%) during the interaction phase. Respective AUC_SS values for R-warfarin were 7.31 mg · h · l⁻¹ (43.8%) and 7.58 mg · h · l⁻¹ (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory. Received: 13 May 1996 / Accepted in revised form: 29 August 1996     

Retrospective evaluation of a possible interaction between warfarin and levofloxacin

STUDY OBJECTIVES: In order to clarify the clinical significance of a suspected drug interaction, we sought to determine if the international normalized ratio (INR) is affected when levofloxacin is administered in patients receiving long-term warfarin therapy. DESIGN: Retrospective cohort study using pharmacy and medical records. SETTING: Outpatient clinic. PATIENTS: Forty-three patients receiving long-term warfarin therapy who subsequently were prescribed either levofloxacin (22 patients) or felodipine (21 controls); felodipine was chosen as it has been shown not to interact with warfarin. Patients in both groups were required to have a documented INR before the start of levofloxacin or felodipine (pre-INR) and either during levofloxacin or felodipine therapy or within 15 days after the drug had been started (post-INR). MEASUREMENTS AND MAIN RESULTS: Patient demographics were similar between the two treatment groups. The mean +/- SD age of the patients in the levofloxacin and control groups was 59.5 +/- 8.7 and 65.3 +/- 11.5 years, respectively (p=0.07). The mean change between the pre- and post-INR (primary outcome measure) was 0.31 +/- 0.82 (pre-INR 2.46, post-INR 2.76) and 0.21 +/- 0.54 (pre-INR 2.46, post-INR 2.67) in the levofloxacin and felodipine groups, respectively (p=0.65). A post hoc power analysis, based on a sample-derived, weighted standard deviation of 0.68, revealed that the study had 66% power to detect a change of 0.5 in the INR value. The percentage of patients who required a warfarin dosage adjustment based on the post-INR (secondary outcome measure) was 41% (9 of 22 patients) in the levofloxacin group and 33% (7 of 21 patients) in the felodipine group. CONCLUSION: Although our primary analysis did not detect a warfarin-levofloxacin interaction, the potential for such an interaction, especially in idiosyncratic cases, cannot be ruled out. Clinicians should closely monitor INR values when levofloxacin is administered jointly with warfarin.     

Pharmacodynamic evaluation of warfarin and rosuvastatin co-administration in healthy subjects

Objective: To determine whether co-administration of rosuvastatin alters the pharmacodynamics of warfarin, thereby requiring additional monitoring of the anticoagulant effects of warfarin. Methods: In this open-labeled, placebo-controlled, randomized, two-period, crossover trial with a washout period of 15 days, 12 healthy male volunteers were administered daily oral doses of 5 mg warfarin for 14 days. Either rosuvastatin 40 mg/day (treatment A) or placebo (treatment B) was concomitantly administered on days 8–14. The pharmacodynamic parameters prothrombin time (PT) and international normalized ratio (INR) were evaluated on all 14 days pre-dose during both study periods. On the 8th, 10th, 12th, and 14th days of each study period, PT and INR were also measured at 4 h post-dose of rosuvastatin or placebo. Bleeding time and clotting time were assessed on the 1st, 8th, and 14th days pre-dose. Results: Data of 10 subjects have been analyzed. No significant effect of rosuvastatin was seen on the steady-state pharmacodynamics of warfarin during concomitant administration. Conclusion: Rosuvastatin did not significantly alter the anticoagulant effects of warfarin in this study.     

Anticoagulation-related outcomes in patients receiving warfarin after starting levofloxacin or gatifloxacin

STUDY OBJECTIVE: To compare anticoagulation-related outcomes in patients receiving stable dosages of warfarin who started levofloxacin or gatifloxacin therapy. DESIGN: Retrospective medical record review. SETTING: Veterans Affairs medical center. PATIENTS: Of 92 patients receiving the same dosages of warfarin for at least 4 weeks before starting antibiotic therapy, 54 received levofloxacin between January and September 2003, and 38 received gatifloxacin between January and September 2004. MEASUREMENTS AND MAIN RESULTS: Data were obtained through the hospital's pharmacy, laboratory, and general patient databases and through electronic medical records. The INRs evaluated were prefluoroquinolone use, defined as the last INR measured before the start of antibiotic therapy (up to 4 wks earlier), and postfluoroquinolone use, defined as any INR measured during antibiotic therapy through 1 week after discontinuation of the antibiotic. Analyzed outcomes included the percentage of patients with postfluoroquinolone INRs that were above 4, that exceeded the therapeutic goal, or that exceeded the goal by more than 1 point; INR changes of more than 0.5, 1, or 1.5 points above the INR before fluoroquinolone use; major or minor bleeding events; requirement for vitamin K administration; warfarin dosage reduction or withholding doses; and warfarin-related hospital, emergency, or urgent care admissions or visits. No significant differences were noted in baseline characteristics with regard to age, sex, prefluoroquinolone INR, or anticoagulation indications between the two groups. The percentage of patients with a postfluoroquinolone INR above 4 was 2% (1 of 54 patients) in the levofloxacin group versus 21% (8 of 38 patients) in the gatifloxacin group (p=0.003). The percentage of patients receiving vitamin K in the levofloxacin and gatifloxacin groups was 0% (0 of 54 patients) and 11% (4 of 38, p=0.026), respectively. For the other anticoagulation-related outcomes, no significant differences were noted between the groups. CONCLUSION: Patients receiving warfarin who take gatifloxacin may be at higher risk for an INR above 4 compared with those taking levofloxacin. Close monitoring of warfarin therapy while concomitantly receiving gatifloxacin is warranted.     

An observational study examining the impact of capecitabine on warfarin antithrombotic activity and bleeding complications

OBJECTIVE: The objectives of this study are to quantify the frequency of concomitant use of capecitabine and warfarin, and to quantify the rate of bleeding events and elevated international normalized ratio (INR) among concomitant users of warfarin and capecitabine. RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based study within the Henry Ford Health System (Detroit, MI) and the Kaiser Permanente Medical Care Program of Northern California (Oakland, CA). The study population included patients prescribed concomitant capecitabine and warfarin from 1 April 1997 through 31 July 2002. Data from the medical records of concurrent users were extracted through 31 August 2002. MAIN OUTCOME MEASURES: Concomitant use of capecitabine and warfarin, bleeding events, and INR laboratory results, collected from computerized databases and medical record review. RESULTS: Overall, 11% of capecitabine users also received warfarin (99 / 883). Among 17 patients who received warfarin for venous access device prophylaxis, one bleeding event occurred during concomitant capecitabine/warfarin use (rate = 35.7 bleeding events per 100 person-years, 95% confidence interval [CI] 0.9-198.9), and no events occurred during use of warfarin alone (95% CI 0.0-136.2) (p = 0.50). Among patients prescribed warfarin for indications other than port prophylaxis, no bleeding events occurred during concomitant use of capecitabine and warfarin (95% CI 0.0-34.6), and one event occurred during warfarin use alone (rate = 9.2 bleeding events per 100 person-years, 95% CI 0.2-51.3) (p = 0.54). We found one INR elevation > 3.0 among concomitant capecitabine/warfarin users receiving warfarin for port prophylaxis (rate = 35.7 per 100 person-years) and no INR elevations > 3.0 during use of warfarin alone (p = 0.46). Among patients using warfarin for indications other than port prophylaxis, the rates of INR > 3.0 were 309.7 per 100 person-years (95% CI 213.2-434.9) during concomitant capecitabine/warfarin use and 193.5 events per 100 person-years (95% CI 119.8-295.8) during use of warfarin alone (p = 0.09). CONCLUSIONS: The results of our study show a low prevalence of capecitabine and warfarin concomitant use. We did not find large differences in the rates of bleeding events and elevated INR in patients receiving concomitant capecitabine and warfarin when compared with use of warfarin alone. While these results do not imply a lack of biologic interaction, our findings indicate that patients appear to be appropriately managed in clinical practice.     

Warfarin-5-FU interaction--a consecutive case series

Five patients from a single institution received concomitant warfarin and 5-fluorouracil (5-FU) during a 3-year period. The mean weekly warfarin dose before starting chemotherapy was 40.66 mg and during chemotherapy it was 24 mg (p=0.0026). All patients required a warfarin dosage reduction (range 18-74%, mean 44%). Two patients were hospitalized, one with a major retroperitoneal bleed, the other for fresh-frozen plasma administration and observation. Maximum international normalized ratios (INRs) ranged from 3.66-23.7. This series confirms a common, clinically significant interaction between warfarin and 5-FU. An interaction between capecitabine, the orally available prodrug of 5-FU, and warfarin also has been reported. We recommend weekly monitoring of prothrombin time and INR for all patients receiving concomitant warfarin and 5-FU or capecitabine.     

1例吉非替尼与华法林相互作用的案例报道及文献分析

目的 结合实际案例,对吉非替尼与华法林联用时华法林的剂量调整进行文献检索和分析,为给药方案的优化提供参考。方法 报道1例病例,同时查阅国内外相关文献并进行综述分析。结果 本例患者在合并使用吉非替尼26 d后,INR值明显升高（5.23）,停药后调整华法林剂量,将INR值控制在目标范围内。文献综述分析提示,吉非替尼及表皮生长因子受体酪氨酸激酶抑制剂与华法林联用时,有一部分人群可能会出现INR值升高,出血风险增加。结论 华法林和表皮生长因子受体酪氨酸激酶抑制剂联合使用时,建议在启用以及停药后,增加INR的监测频率,及时调整华法林剂量。     

Effect of oseltamivir treatment on anticoagulation: a cross-over study in warfarinized patients

AIM

To investigate whether oseltamivir enhances the anticoagulant effect of warfarin and to evaluate any pharmacokinetic (PK) interaction between the agents.

METHODS

Twenty volunteers (mean age 62 years) receiving daily warfarin and with INR values of 2.0–3.5 during the previous 2 weeks were randomized to concomitant oseltamivir 75 mg twice daily for 4.5 days or warfarin alone in a two-way cross-over design with a 4–8 day wash-out. Anticoagulant effects were assessed by calculating overall [AUEC(0,96 h)] and observed maximum effect (E_max) increase from baseline in INR, decrease from baseline in factor VIIa, and change in vitamin K₁ concentrations. Plasma pharmacokinetics of (R)- and (S)-warfarin and oseltamivir were also assessed.

RESULTS

For both treatments, changes in INR and factor VIIa during treatment were small; for net AUEC(0,96 h), least square mean values were −9.53 (oseltamivir + warfarin) and −1.69 h (warfarin alone) for INR (difference −7.84 h, 90% CI −18.86, 3.17 h), and 1.56 and 0.54 kIU l⁻¹ h, respectively, for factor VIIa (difference, 1.01 kIU l⁻¹ h; 90% CI −1.18, 3.21). Differences between the treatments in E_max increase from baseline for INR, decrease from baseline for factor VIIa and change from baseline in vitamin K₁ concentration were not statistically significant. Oseltamivir did not alter warfarin pharmacokinetics. Oseltamivir was well tolerated in this study with no clinically significant adverse safety findings.

CONCLUSION

Concomitant administration of oseltamivir for 4.5 days to volunteers on daily warfarin had little or no effect on warfarin pharmacokinetics and no effect on pharmacodynamics.     

Vitamin K-independent warfarin resistance after concurrent administration of warfarin and continuous enteral nutrition

STUDY OBJECTIVE: To assess the influence of withholding continuous enteral nutrition for 1 hour before and after warfarin administration compared with the coadministration of warfarin with continuous enteral nutrition on changes in international normalized ratios (INRs). DESIGN: Retrospective, crossover case series. SETTING: Intensive care units of a university-affiliated medical center. PATIENTS: Six adults who required nutritional support for at least the first 10 consecutive days of warfarin therapy; during that 10-day period, they had a period of at least 3 consecutive days during which the enteral feeding was withheld for 1 hour before and after warfarin administration, and had a period of at least 3 consecutive days when feedings were not withheld during warfarin administration. Patients with advanced liver disease and those who received therapies, during the observation period, that significantly alter warfarin metabolism were omitted from the study. MEASUREMENTS AND MAIN RESULTS: The change in INR during the 3-day observation period when feedings were withheld for 1 hour before and after warfarin administration was significantly different versus the change in INR during coadministration of warfarin with continuous feeding (mean +/- SD 0.74 +/- 0.66 vs -0.13 +/- 0.81, p < or = 0.05). This difference in INR response occurred despite the administration of similar dosages of warfarin (5.6 +/- 2.1 vs 5.7 +/- 2.1 mg/day, p>0.05). Also noted was a clinically irrelevant, but statistically significant, difference in vitamin K intake between treatment periods (77 +/- 36 mug/day when feedings were withheld vs 102 +/- 28 microg/day when feedings were not withheld, p < or = 0.05). CONCLUSION: Continuous enteral nutrition should be withheld for 1 hour before and after warfarin administration to prevent enteral nutrition-associated warfarin resistance.     

Effect of oral diuretics on chronic warfarin therapy: a retrospective study

Background: Limited clinical documentation is suggestive of a drug interaction between warfarin and diuretics.

Objective: To evaluate the effect on international normalized ratio (INR) when a daily oral diuretic is started or increased in patients on chronic stable warfarin therapy.

Methods: The medical records of all active patients of two hospital-based anticoagulation clinics were retrospectively reviewed to identify patients who were started on or received a dose increase of a daily oral diuretic while on stable warfarin therapy. The primary endpoint was the mean difference between an INR recorded within 30 days prior to the diuretic initiation (pre-INR) and an INR recorded within 30 days after diuretic initiation (post-INR).

Results: A total of 1254 patient charts were screened and a total of 123 patients met the study criteria. The mean difference in pre-INR and post-INR was 0.09 (95% CI -0.03 to 0.21, p = 0.12). Post-INR values were outside of the patient's therapeutic range in 39 patients (32%), but no major bleeding or thromboembolic events were reported.

Conclusion: Based on this retrospective study, diuretics did not result in a significant change in the INR in patients on stable warfarin therapy.     

AM Versus PM Postoperative Administration of Warfarin With a Mechanical Mitral Valve

Background: Currently, there are no guidelines regarding the optimal daily timing of inpatient warfarin administration. Objective: The purpose of this study was to determine whether dosing warfarin in the morning will have a significant impact on therapeutic international normalized ratio (INR) achievement compared with evening administration in mechanical mitral valve patients initiated on warfarin following cardiac surgery. Methods: This was a single-center, pre- and post-retrospective cohort conducted between 2014 and 2018. One-hundred fifty-four adult patients who underwent a mechanical mitral valve replacement or alternative cardiac surgery with a history of a mechanical mitral valve were enrolled. The primary outcome was achievement of therapeutic INR at any time point after initiation of warfarin. Pre-intervention administration timing was 6 pm and post-intervention timing was 10 am. Results: Baseline characteristics including age, sex, and race were similar between the 2 groups (P = NS for each characteristic). Therapeutic INR achievement was significantly improved at all time points following 10 am warfarin administration compared with 6 pm (hazard ratio = 1.69; P = .005). Mean time-to-therapeutic INR was 7.37 days in the post-intervention group and 8.39 days in the pre-intervention group (P = .073). There were no significant differences in INR >4, bleeding, or thrombotic complications between groups. Conclusion and Relevance: This retrospective analysis suggests that there may be a postoperative benefit in therapeutic INR achievement in mechanical valve patients when dosing warfarin in the morning compared with evening administration. Large-scale studies should be conducted to further elucidate the potential benefit across more heterogeneous populations.     

Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin

Objective To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK₁)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting.Methods This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10–12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1–3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day –1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily.Results The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC_0-24h and C_max. However, compared with placebo, trough S(–) warfarin concentrations decreased on days 5–8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011).Conclusion These data are consistent with a significant induction of CYP2C9 metabolism of S(–) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7–10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.     

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin

Objectives: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. Methods: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5–10 mg on days 2–21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15–21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C_max), time to reach C_max (t_max), the area under the concentration–time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C_min of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). Results: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C_min concentrations of S-warfarin and irbesartan were also not affected. Conclusions: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary. Received: 10 December 1998 / Accepted in revised form: 29 June 1999     

低剂量华法林对心房颤动患者脑卒中和凝血指标的影响

目的 探讨心房颤动患者低剂量长期使用华法林对患者脑卒中和凝血指标的影响。方法 选择2016年1月—2018年12月喀什地区第一人民医院收治的心房颤动患者213例作为研究对象,按照随机数字表法将患者分为3组,每组各71例。对照组患者使用阿司匹林肠溶片,200 mg/d。华法林高剂量组患者在使用华法林钠片前测定抗凝强度国际化标准比率（INR）作为基础值,初始剂量为2.5 mg/d,每隔3~5 d复查IRN,根据IRN调整使用剂量,每次增加0.625 mg,直至复查INR达标,达标时IRN值为2.1~3.0。华法林低剂量组患者使用华法林初始量为1.25 mg/d,每隔3~5 d复查IRN,达标时IRN值为1.5~2.0。根据IRN调整使用剂量,如果INR<1.5,每次增加0.625 mg,直至复查INR达标;如果INR>2.1,将华法林剂量减少0.625 mg。INR不稳定时,连续达标2次后以该剂量作为维持剂量,每月复查1次,直至INR达标。3组均治疗随访18个月。观察并比较两组患者的脑卒中发生情况、凝血指标、华法林用量、达INR标准时间和不良反应发生情况。结果 随访后,华法林高剂量组脑卒中发生率为2.82%,华法林低剂量组为4.23%,均明显低于对照组的14.08%,组间差异具有统计学意义（P<0.05）。治疗后,3组活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）均明显延长（P<0.05）,华法林高剂量和低剂量APTT、PT显著优于对照组,组间差异具有统计学意义（P<0.05）。华法林低剂量组华法林使用量和INR达标准值时间均明显低于华法林高剂量组（P<0.05）。治疗期间,华法林高剂量组出血、腹部不适等不良反应发生率为9.86%,华法林低剂量组为5.63%,均明显低于对照组的29.58%（P<0.05）。结论 心房颤动患者长期使用低剂量华法林能够有效的达到预防脑卒中的效果,其疗效与标准抗凝强度相当,且明显优于阿司匹林,具有较高的临床应用价值,可推广使用。     

Drug interaction between capecitabine and warfarin: a case report and review of the literature

OBJECTIVE: To report on possible adverse interaction between capecitabine and warfarin in a patient with cancer, who developed subconjunctival and nose bleeding during treatment with these drugs and review of the previously reported five cases in the literature. CASE SUMMARY: In the second week of capecitabine treatment the patient was hospitalized owing to subconjunctival hemorrhage and nose bleeding. Her international normalized ratio (INR) level was found to have increased, and both drugs were discontinued. Fresh frozen plasma replacement was administered. Warfarin and capecitabine treatment were restarted again but the warfarin dose was decreased. The patients INR was kept between 2.5-3 with the reduced dose of warfarin. DISCUSSION: Capecitabine is an orally active prodrug of fluorouracil (FU) and is extensively used as an antineoplastic agent. It is converted to 5-FU in the liver and tumor tissues. Warfarin is an antithrombolytic agent and is metabolized by liver cytochorom P450 (CYP) isoenzymes in liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of CYP. However, the concomitant administration of capecitabine and warfarin resulted in gastrointestinal, retroperitoneal bleeding and hemorrhagic blisters in the five cases previously reported. The exact mechanism of this interaction is unknown; however, a significant pharmacokinetic interaction between capecitabine and S-warfarin resulting in exaggerated anticoagulant activity has recently been demonstrated. Here, we describe another case and use of the Naranjo adverse drug reaction (ADR) probability scale, which indicated a probable relationship between subconjunctival bleeding and epistaxis in this patient after concomitant warfarin and capecitabine use. CONCLUSION: Capecitabine is extensively used in outpatient clinics, and physicians should be aware of ADRs arising from combined used of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using this medication regimen.     

Utilization review of concomitant use of potentially interacting drugs in Thai patients using warfarin therapy

PURPOSE: In Thailand, there has been no study determining the concomitant use of medications, known to potentially interact with warfarin, in patients receiving warfarin therapy. This paper examined the frequency of which specific interacting drugs were concomitantly used in warfarin users. METHODS: We retrospectively examined the database of warfarin outpatient medical records from a regional 756-bed hospital located in the north of Thailand. All patients receiving warfarin from 10 June 1999 to 4 August 2004 were reviewed to identify all drugs possessing interaction potential with warfarin. The potential of significant interactions were divided into high, moderate and low, according to the extent of evidence documented in textbooks and literature. RESULTS: Among 1093 patients receiving warfarin therapy, 914 (84%) patients received at least one potentially interacting drug and half of them (457 patients) received at least one drug with high potential for interaction. The most frequently concomitant drug that increased INR was acetaminophen (63%, 316/457). Propylthiouracil was the most frequently concomitant drug that decreased INR response (4%, 19/457), while diclofenac was the most frequently concomitant drug that increased bleeding risk (16%, 73/457). CONCLUSIONS: About a half of patients receiving warfarin therapy was prescribed concomitant drug(s) that has a high potential of interactions with warfarin. These patients should be closely monitored and counselled to watch for signs and symptoms of bleeding and thrombosis to avoid adverse events associated with drug interactions.     

Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe.

Evidence for the selectivity of S-warfarin metabolism by CYP2C9 is substantial, suggesting that warfarin may be a potential CYP2C9 phenotyping probe. It is, however, limited by its ability to elevate the international normalized ratio (INR) and potentially cause bleeding. The effect of vitamin K to attenuate the elevation of INR may enable the safe use of warfarin as a probe. The objective of this study was to investigate the pharmacokinetics and pharmacodynamics of S- and R-warfarin in plasma following the administration of warfarin alone versus warfarin and vitamin K in CYP2C9*1 homozygotes. Healthy adults received, in a randomized crossover fashion in a fasted state, warfarin 10 mg orally or warfarin 10 mg plus vitamin K 10 mg orally. Blood samples were obtained over 5 days during each phase. INR measurements were obtained at baseline and day 2 in each phase. INR, AUC0-infinity, and t1/2 of plasma S- and R-warfarin were examined. Eleven CYP2C9*1 homozygotes (3 men, 8 women) were enrolled. INR at day 2 following warfarin 10 mg was 1.18 +/- 0.19, which differed significantly from baseline (INR = 1.00 +/- 0.05) and warfarin with vitamin K (INR = 1.06 +/- 0.07). INR at baseline was not significantly different from warfarin with vitamin K. t1/2 and AUC0-infinity of both enantiomers did not significantly differ between the phases. It was concluded that INR is apparently attenuated by concomitant administration of a single dose of vitamin K without affecting the pharmacokinetics of either warfarin stereoisomer. Warfarin 10 mg may be safely used as a CYP2C9 probe in *1 homozygotes when given concomitantly with 10 mg of oral vitamin K.     

In silico evaluation of warfarin–bucolome therapy

Purpose: Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter‐patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach. Methods: In vitro data regarding the enzymatic kinetics of (S)‐warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)‐warfarin and its inter‐patient variation (assessed using the standard deviation of its natural logarithm (σ)) were predicted using a physiologically based population pharmacokinetic simulator (Simcyp^TM) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and σ values predicted under various conditions (the prediction study). Results and Discussion: The σ values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter‐patient variation, as clinically observed. In the prediction study, the σ value of the bucolome co‐administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter‐patient variation of (S)‐warfarin pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd.