Drug interactions between Miradon and Prevpac

clarithromycin ↔ anisindione

Applies to:Prevpac (amoxicillin/clarithromycin/lansoprazole) and Miradon (anisindione)

MONITOR CLOSELY: Coadministration with clarithromycin or erythromycin may infrequently but substantially enhance the hypoprothrombinemic effect of warfarin and other coumarin anticoagulants. The exact mechanism of interaction is unknown. Data from clinical studies have not supported a significant, predictable pharmacodynamic or pharmacokinetic interaction in general. Although both macrolides are potent inhibitors of CYP450 3A4 and can inhibit metabolism of the R(+) enantiomer of warfarin, the overall effect on racemic warfarin pharmacokinetics appears to be minor. In 12 normal subjects, the clearance of warfarin (1 mg/kg single dose) decreased by an average of 14% following pretreatment with erythromycin 250 mg four times a day for 8 days. In a study of eight patients stabilized on warfarin, the addition of erythromycin led to only a small increase in the effect of warfarin. Nevertheless, a population-based cohort study focusing on antibiotic use in outpatients treated with phenprocoumon or acenocoumarol at a Netherlands anticoagulant clinic identified clarithromycin use as a risk factor for overanticoagulation (INR greater than or equal to 6), even after adjustment for potential confounding factors. There have also been case reports of increased prothrombin time or INR and/or serious bleeding complications in patients stabilized on coumarin therapy following the addition of erythromycin or clarithromycin. The UK Committee on Safety of Medicines reported on a woman taking warfarin who suffered a fatal cerebrovascular bleed 3 days after starting clarithromycin. However, other influences such as fever, infection, malnutrition, and other concomitant underlying conditions on clotting mechanisms and coumarin pharmacokinetics should also be considered.

MANAGEMENT: Given the potential for clinically significant interaction and even fatality in the occasional, susceptible patient, close monitoring is recommended if clarithromycin or erythromycin is prescribed during coumarin anticoagulant therapy. The INR should be checked frequently and coumarin dosage adjusted accordingly, particularly following initiation or discontinuation of macrolide therapy in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools. The same precaution may be applicable during therapy with other oral anticoagulants (e.g., indandiones) and other similar macrolides (e.g., troleandomycin), although clinical data are lacking.

amoxicillin ↔ anisindione

Applies to:Prevpac (amoxicillin/clarithromycin/lansoprazole) and Miradon (anisindione)

MONITOR: Penicillins may occasionally potentiate the risk of bleeding in patients treated with oral anticoagulants. The exact mechanism of interaction is unknown but may involve penicillin inhibition of platelet aggregation. In one study, defective platelet aggregation occurred with predictability in patients receiving penicillin G 24 million units/day, ampicillin 300 mg/kg/day, and methicillin 300 mg/kg/day. Other penicillins such as nafcillin, piperacillin, and ticarcillin have also been found to affect platelet function, and benzylpenicillin and carbenicillin have been reported to increase bleeding times and cause bleeding in the absence of an anticoagulant. There have been case reports describing increases in prothrombin time and INR as well as spontaneous bruising and bleeding in anticoagulated patients following initiation or completion of penicillin therapy. Although most cases have involved large, intravenous doses of some penicillins (e.g., carbenicillin, penicillin G, ticarcillin), the interaction has also been reported with regular, oral doses of amoxicillin and amoxicillin-clavulanate. In fact, a case-control study found amoxicillin-clavulanate to be one of only two medications to significantly increase the risk of overanticoagulation in previously stable outpatients treated with phenprocoumon or acenocoumarol. In that study, 300 outpatients at a Netherlands anticoagulant clinic who presented with an INR value greater than or equal to 6.0 (median value 6.8) were compared with 302 randomly selected matched controls with INR values within the target range (median value 3.2), and changes in the use of 87 potentially interacting drugs or drug classes in the four weeks prior to the index day were identified and analyzed. A course of amoxicillin-clavulanate increased the risk of overanticoagulation even after adjustment for potential confounding factors, particularly in patients treated with acenocoumarol. A follow-up study focusing on antibiotic use in outpatients treated with phenprocoumon or acenocoumarol at a different Netherlands anticoagulant clinic also identified amoxicillin use as a risk factor for overanticoagulation, with the relative risk most strongly increased four days or more after start of the antibiotic.

MANAGEMENT: Caution is recommended if a penicillin is prescribed during oral anticoagulant therapy, especially in the elderly and patients with uremia or hepatic impairment. The INR should be checked frequently and anticoagulant dosage adjusted accordingly, particularly following initiation or discontinuation of penicillin therapy in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

anisindione ↔ lansoprazole

Applies to:Miradon (anisindione) and Prevpac (amoxicillin/clarithromycin/lansoprazole)

MONITOR: Coadministration with proton pump inhibitors (PPIs) has occasionally been associated with enhanced hypoprothrombinemic effect of warfarin. The exact mechanism is unknown but may involve PPI inhibition of CYP450 2C19 and/or 3A4, the isoenzymes partially responsible for the metabolic clearance of the biologically less active R(+) enantiomer of warfarin. There have been reports of increased INR and prothrombin time in patients receiving warfarin with various commercially available proton pump inhibitors. However, a significant pharmacokinetic interaction has not been reported. In one study, coadministration of omeprazole 20 mg/day and warfarin (individualized dosage) in 21 healthy, young men for 2 weeks resulted in a 12% increase in the mean plasma concentration of R(+) warfarin compared to coadministration with placebo. Plasma concentrations of the S(-) enantiomer were unaffected, and no clinically significant alterations in coagulation times were noted. Similar results were reported in a group of 28 patients on continuous therapy with warfarin given omeprazole 20 mg/day for 3 weeks. Additionally, other studies reported no pharmacokinetic interaction between warfarin and pantoprazole or dexlansoprazole.

MANAGEMENT: Given the potential for interaction and the high degree of interpatient variability with respect to warfarin metabolism, patients should be closely monitored during concomitant therapy with PPIs. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of PPI in patients who are stabilized on their warfarin regimen. The same precaution may be applicable during therapy with other oral anticoagulants. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.