rment bolus dose no reduction in the bolus dose is needed for any degree of renal impairment. maintenance infusion in patients with creatinine clearance less than 30 ml/min (by cockcroft gault equation), reduce the infusion rate to 1 mg/kg/h. in patients on hemodialysis, reduce the infusion rate to 0.25 mg/kg/h [see use in specific populations ( 8.6 ), clinical pharmacology ( 12.3 )] . 2.3 instructions for administration inspection of container parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. once removed from refrigerator, use immediately [see how supplied storage and handling ( 16.2 )] . discard any unused portion. drug compatibilities no incompatibilities have been observed with administration sets. do not administer the drugs listed in table 1 in the same intravenous line with bivalirudin rtu injection. table 1: drugs not for administration in the same intravenous line with bivalirudin rtu injection alteplase amiodarone hcl amphotericin b chlorpromazine hcl diazepam dobutamine prochlorperazine edisylate reteplase streptokinase vancomycin hcl

ly dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. for these reasons, comparison of the incidence of antibodies to bivalirudin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. in in vitro studies, bivalirudin exhibited no platelet aggregation response against sera from patients with a history of hit/hitts. among 494 subjects who received bivalirudin in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. nine additional patients who had initial positive tests were negative on repeat testing. 6.2 postmarketing experience because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following adverse reactions have been identified during post-approval use of bivalirudin: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during pci with and without intracoronary brachytherapy, including reports of fatal outcomes; pulmonary hemorrhage; cardiac tamponade; and inr increased.

ats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). these studies revealed no harm to the fetus attributable to bivalirudin. at 500 mg/kg/day subcutaneously, litter sizes and live fetuses in rats were reduced. fetal skeletal variations were also noted. some of these changes could be attributed to maternal toxicity observed at high doses. 8.2 lactation risk summary it is not known whether bivalirudin is present in human milk. no data are available on the effects of bivalirudin on the breastfed child or on milk production. 8.4 pediatric use the safety and effectiveness of bivalirudin in pediatric patients have not been established. 8.5 geriatric use in studies of patients undergoing pci, 44% were ≥65 years of age and 12% of patients were ≥75 years old. elderly patients experienced more bleeding events than younger patients. 8.6 renal impairment the disposition of bivalirudin was studied in ptca patients with mild, moderate and severe renal impairment. the clearance of bivalirudin was reduced approximately 21% in patients with moderate and severe renal impairment and was reduced approximately 70% in dialysis-dependent patients [see clinical pharmacology ( 12.3 )] . the infusion dose of bivalirudin rtu injection may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see dosage and administration ( 2.2 )] .

50 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). these studies revealed no harm to the fetus attributable to bivalirudin. at 500 mg/kg/day subcutaneously, litter sizes and live fetuses in rats were reduced. fetal skeletal variations were also noted. some of these changes could be attributed to maternal toxicity observed at high doses.

ivity as evidenced by prolongation of the act, aptt, pt, and tt. intravenous administration of bivalirudin produces an immediate anticoagulant effect. coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration. bivalirudin also increases inr. in 291 patients with ≥70% vessel occlusion undergoing routine ptca, a positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving act values of 300 sec or 350 sec. at a bivalirudin dose of 1 mg/kg intravenous bolus plus 2.5 mg/kg/h intravenous infusion (1.4 times higher than the approved dose of 1.75 mg/kg/h) for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal act values greater than 300 sec. 12.3 pharmacokinetics bivalirudin exhibits linear pharmacokinetics following intravenous administration to patients undergoing ptca. in these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/ml is achieved following an intravenous bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h intravenous infusion. distribution bivalirudin does not bind to plasma proteins (except thrombin) or to red blood cells. elimination bivalirudin has a half-life of 25 minutes in ptca patients with normal renal function. the total body clearance of bivalirudin in ptca patients with normal renal function is 3.4 ml/min/kg. metabolism bivalirudin is metabolized by proteolytic cleavage. excretion bivalirudin undergoes glomerular filtration. tubular secretion and tubular reabsorption are also implicated in the excretion of bivalirudin, although the extent is unknown. specific populations patients with renal impairment total body clearance was similar for ptca patients with normal renal function and with mild renal impairment. clearance was reduced by 21% in patients with moderate and severe renal impairment with a half-life of 34 and 57 minutes, respectively. in dialysis patients, clearance was reduced by 70%, with a half-life of 3.5 hours. approximately 25% bivalirudin is cleared by hemodialysis.

nd with mild renal impairment. clearance was reduced by 21% in patients with moderate and severe renal impairment with a half-life of 34 and 57 minutes, respectively. in dialysis patients, clearance was reduced by 70%, with a half-life of 3.5 hours. approximately 25% bivalirudin is cleared by hemodialysis.

ne hour prior to randomization. the studies did not demonstrate that bivalirudin was statistically superior to heparin for reducing the risk of death, mi, abrupt closure of the dilated vessel, or clinical deterioration requiring revascularization or placement of an aortic balloon pump, but the occurrence of these events was similar in both treatment groups. study outcomes are shown in table 2 . table 2: incidences of in-hospital endpoints in bat trial † a composite of death or mi or clinical deterioration of cardiac origin requiring revascularization or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure. endpoint bivalirudin (n=2161) heparin (n=2151) primary endpoint † 7.9% 9.3% death, mi, revascularization 6.2% 7.9% death 0.2% 0.2% mi 3.3% 4.2% at-bat trial (nct# 00043940) this was a single-arm open-label study in which 51 subjects with heparin-induced thrombocytopenia (hit) or heparin induced thrombocytopenia and thrombosis syndrome (hitts) undergoing pci. the majority of patients achieved adequate act at the time of device activation and no major bleeding was reported. two patients developed thrombocytopenia.