h the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

nd heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure. if prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology. there is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. cases of infusion site reactions have been reported with intravenous milrinone therapy (see adverse reactions ). consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.

inuous intravenousinfusion standard 0.50 mcg/kg/min 0.77 mg/kg maximum 0.75 mcg/kg/min 1.13 mg/kg the infusion rate should be adjusted according to hemodynamic and clinical response. patients should be closely monitored. in controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure. note: see “dosage adjustment in renally impaired patients.” dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. duration of therapy should depend upon patient responsiveness. the maintenance dose in ml/hr by patient body weight (kg) may be determined by reference to the following table. milrinone infusion rate (ml/hr) using 200 mcg per ml concentration maintenance dose(mcg/kg/min) patient body weight (kg) 30 40 50 60 70 80 90 100 110 120 0.375 3.4 4.5 5.6 6.8 7.9 9 10.1 11.3 12.4 13.5 0.400 3.6 4.8 6 7.2 8.4 9.6 10.8 12 13.2 14.4 0.500 4.5 6 7.5 9 10.5 12 13.5 15 16.5 18 0.600 5.4 7.2 9 10.8 12.6 14.4 16.2 18 19.8 21.6 0.700 6.3 8.4 10.5 12.6 14.7 16.8 18.9 21 23.1 25.2 0.750 6.8 9 11.3 13.5 15.8 18 20.3 22.5 24.8 27 dosage adjustment in renally impaired patients data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 ml/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. reductions in infusion rate may be necessary in patients with renal impairment. for patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table: creatinine clearance (ml/min/1.73 m 2 ) infusion rate (mcg/kg/min) 5 0.20 10 0.23 20 0.28 30 0.33 40 0.38 50 0.43 parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. milrinone lactate in 5% dextrose injection is a clear, colorless to pale yellow solution. directions for use when administering milrinone lactate in 5% dextrose injection by continuous infusion, it is advisable to use a calibrated electronic infusion device. to open tear overwrap down side at slit and remove solution container. some opacity of the plastic due to moisture absorption during the sterilization process may be observed. this is normal and does not affect the solution quality or safety. the opacity will diminish gradually. after removing overwrap, check for minute leaks by squeezing inner bag firmly. if leaks are found, discard solution as sterility may be impaired. preparation for administration visually inspect the container. if the administration port is damaged, detached, or not present, discard container as solution path sterility may be impaired. (use aseptic technique) 1. suspend container from eyelet support. 2. remove top portion of twist off port at bottom of container. 3. attach administration set. refer to complete directions accompanying set. caution : do not administer simultaneously with blood. do not use plastic containers in series connections. such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

not been related to the dose or plasma milrinone concentration. other cardio vascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%. in the post-marketing experience, there have been rare cases of “torsades de pointes” reported. cns effects headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone. other effects other adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%. post-marketing adverse event reports in addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone: isolated spontaneous reports of bronchospasm and anaphylactic shock. liver function test abnormalities and skin reactions such as rash. administration site conditions: infusion site reaction. to report suspected adverse reactions, contact gland pharma at 864-879-9994 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

left ventricular pressure. studies in normal subjects have shown that milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug. both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/ml to 300 ng/ml. in addition to increasing myocardial contractility, milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation. the acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. the total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related. pharmacokinetics following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone had a volume of distribution of 0.38 liters/kg , a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. these pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent. milrinone has been shown (by equilibrium dialysis) to be approximately 70 % bound to human plasma protein. the primary route of excretion of milrinone in man is via the urine. the major urinary excretions of orally administered milrinone in man are milrinone (83%) and its o-glucuronide metabolite (12%). elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following do sing and approximately 90% recovered within the first eight hours following dosing. the mean renal clearance of milrinone is approximately 0.3 liters/min, indicative of active secretion. pharmacodynamics in patients with heart failure due to depressed myocardial function, milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. additionally, there is no increased effect on myocardial oxygen consumption. in uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone was accompanied by clinical symptomatic improvement, but the ability of milrinone to relieve symptoms has not been evaluated in controlled clinical trials. the great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy. in studies in congestive heart failure patients, milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). a smaller number of patients have received infusions of milrinone for periods up to 72 hours without evidence of tachyphylaxis. the duration of therapy should depend upon patient responsiveness. milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone may increase ventricular response rate because of its slight enhancement of av node conduction. in these cases, digitalis should be considered prior to the institution of therapy with milrinone. improvement in left ventricular function in patients with ischemic heart disease has been observed. the improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia. the steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/ml. near maximum favorable effects of milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/ml to 250 ng/ml range.

es up to 32 mg/kg/day.