Bosentan applied in a single dose of 2400 mg in healthy volunteers, and 2000 mg / day for 2 months in patients with other diseases, in addition . The most common symptoms of overdose was headache of mild or moderate intensity. Overdose can lead to a marked decrease in blood pressure, which may require medical treatment. Joined case bosentan overdose teenage boy after taking 10,000 mg, which halo steroid resulted in marked nausea, vomiting, marked reduction in blood pressure, dizziness, sweating, a violation of sharpness of vision. State fully returned to normal within 24 hours, while the correction of pronounced reduction in blood pressure. Bosentan is not removed by hemodialysis.
Interaction with other drugs
Bosentan is metabolized with participation of cytochrome isoenzymes . Inhibition increase the plasma concentration of bosentan (see. Ketoconazole). Effect of inhibition isoenzymes at concentrations of bosentan plasma have not studied. The combined use with caution. Concomitant use with fluconazole, which basically has an inhibitory effect on the isozyme and only a small – on the isoenzyme bosentan may cause a higher concentration in plasma. This combination is not recommended. For the same reason it is not recommended the simultaneous use and potent inhibitors isoenzyme (such as ketoconazole, itraconazole or ritonavir) and an inhibitor isoenzymes (such as voriconazole).
Bosentan is an inducer isoenzymes . According to a study in vitro it assumed the role of inductor isoenzyme . Therefore, while use and drugs the metabolism of which is mediated by these isoenzymes, their concentration in the blood plasma decreases. Keep in mind the possibility of reducing the effectiveness of drugs, the metabolism of which is carried out with the participation of these same isoenzymes. You may need a dosage adjustment simultaneously used drugs after you start taking , change the dose or withdrawal.
Cyclosporine: the simultaneous use halo steroid and cyclosporine (a calcineurin inhibitor) is contraindicated. With this combination of drugs bosentan minimum the initial concentration in the blood plasma increased 30 times as compared to using bosentan in monotherapy. Bosentan equilibrium concentration in plasma increased 3-4 times as compared with the concentration of bosentan in monotherapy. Possible mechanism of this interaction is inhibited by cyclosporin transport protein responsible for the delivery of bosentan in hepatocytes. Plasma concentration of cyclosporin thus reduced by approximately 50%.
Tacrolimus, Sirolimus: simultaneous application in clinical trials have not been studied, but it is assumed that bosentan plasma concentration can be increased by analogy with cyclosporine.Plasma concentrations of tacrolimus and sirolimus may be reduced when combined . In this regard, not be used simultaneously with the tacrolimus or sirolimus. If necessary, the application of this combination control is required and the patient’s condition tacrolimus and sirolimus concentration in the blood plasma.
Glibenclamide: while at a dose of 125 mg 2 times / day. for 5 days reduces the concentration of glibenclamide by 40% in blood plasma, which may be accompanied by a significant decrease hypoglycemic effect of glibenclamide. Bosentan concentration in plasma is also reduced by 29%. In addition, patients receiving concomitant treatment, the risk of increased activity of “liver” transaminases. Both active compounds, glibenclamide and bosentan, have an inhibitory effect on the transport pump bile salts, thereby enhancing the activity can be explained by “liver” transaminases. In connection with this, Traklir ® should not be used in conjunction with glibenclamide. No information about possible drug interactions with other sulfonyl-urea derivatives.
Hormonal contraceptives: while the application for 7 days drug halo steroid125 mg 2 times / day. and an oral contraceptive for a single dose – combination product containing 1 mg norethisterone and 35 mcg ethinyl estradiol, noted reduction in AUC for its components by 14% and 31%, respectively. For some patients norethisterone and ethinyl estradiol exposure reduction reached 56% and 66%, respectively.Thus, hormonal contraception can not be considered effective, regardless of the route of administration -Inside drug injection, transdermally or in the form of implants.
Warfarin: while the application in healthy volunteers with at a dose of 500 mg 2 times / day. for 6 days decreased the concentration in blood plasma by 29% and 38%, respectively. Experience the simultaneous use and warfarin in patients was not accompanied by clinically significant changes in the international normalized ratio and warfarin (at the end of the study compared with baseline). In addition, the frequency adjustment of warfarin dose during the study changes or due to side effects were not different in patients treated with bosentan or placebo. You do not need dose adjustment of warfarin or other oral anticoagulants at the beginning of therapy . However, we recommend mandatory control , especially at the beginning and stages of increasing the dose.
Simvastatin: while the application 2 times / day. reduced concentration of simvastatin and its active form beta-hydroxy acids in blood plasma by 34% and 46%, respectively. The simultaneous use of simvastatin has no effect on the concentration in the blood plasma of bosentan. In a joint application of the drug simvastatin and it is recommended to control the concentration of cholesterol in the blood plasma, with subsequent correction of the dose of simvastatin.
Ketoconazole: simultaneous application dose of 62.5 mg 2 times a day. and ketoconazole, a potent inhibitor of isoenzyme, accompanied by a twofold increase in bosentan plasma concentrations. Correction dose is not carried out.
Increase bosentan plasma concentrations is also expected, while the use of itraconazole and ritonavir, despite the lack of confirmation in studies in vivo. However, in combination with bosentan inhibitor of halo steroid, patients with reduced metabolism isozyme exists a significant increase in the risk of bosentan concentration that may increase the frequency and severity of side effects of the drug.