Possible drug-drug interaction between high-dose esomeprazole and phenprocoumon.

PURPOSE: It is established that omeprazole increases (R)+ warfarin levels with around 10 %. Whether (es)omeprazole also increase the plasma levels of acenocoumarol or phenprocoumon is still uncertain. We analyzed whether addition of (es)omeprazole to acenocoumarol or phenprocoumon increases the international normalized ratio (INR) levels and the risk of overanticoagulation. METHODS: We analyzed all hospital admissions in four teaching hospitals. Patients who used coumarins and pantoprazole or (es)omeprazole simultaneously for at least four consecutive days were included in the study. We analyzed the highest INR level and whether patients had an INR level above six. We compared patients using omeprazole or esomeprazole with patients using pantoprazole, because for pantoprazole, no interaction has been reported. RESULTS: We analyzed 5747 admissions with 4540 patients using one of the drug combinations. For acenocoumarol (4578 admissions), no significant differences were found between users of esomeprazole, omeprazole, and pantoprazole. For phenprocoumon (1169 admissions), the highest INR measured was significantly higher in users of esomeprazole than in users of pantoprazole (4.7 versus 4.3; p = 0.035). No significant difference was found with omeprazole versus pantoprazole (4.3 versus 4.3; p = 0.66). A non-significant association was found between the esomeprazole dose and the highest INR level (p = 0.055). The risk of an INR above six did not differ significantly between esomeprazole and pantoprazole (27.7 % versus 22.9 %; p = 0.34). CONCLUSIONS: The use of esomeprazole simultaneously with phenprocoumon during hospital admissions might increase the anticoagulant effect. The clinical relevance seems to be limited, because no statistically significant increased risk of overanticoagulation was found.

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.